http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070808/

http://catalog.ninds.nih.gov/ninds/facet/Health-Topics/term/Parkinson-s-Disease

Terri

Misdiagnosis

See above Study on Essential Tremor and Parkinson Disease Link: Lack of a link (keyword alpha-synuclein and lewy bodies)

It appears that the above abstract offers insight into the lewy bodies associated with Parkinson’s that essential tremors mimic the involuntary muscle movements that are generally normal but may be a precursor to more intensive tremors if not prevented. I needed to operationally define Essential Tremor (ET) as a pervasive symptom. However is reversiable according to the literature.

Perhaps a natural antidote can be also have application that addresses the hypothesis that alpha synuclein is based on this study

Parkinson's disease (PD) is characterized as a neurodegenerative movement disorder presenting with rigidity, resting tremor, disturbances in balance and slowness in movement.

An important pathologic feature of PD is the presence of Lewy bodies.

The primary structural component of Lewy bodies are fibrils composed primarily of alpha-synuclein, a highly conserved 140 amino acid protein that is predominantly expressed in neurons and which may play a role in synaptic plasticity and neurotransmission.

Numerous studies suggest the aggregation and modification of alpha-synuclein as a key step leading to Lewy body formation and neuronal cell loss associated with PD.

CNS Neurol Disord Drug Targets. 2012 Mar;11(2):174-9.

Targeting alpha-synuclein for the treatment of Parkinson's disease.

Their recommendation phamacologically is

…Because of the central role of alpha-synuclein in PD, it represents a novel drug target for the possible treatment of this disease. In this review, an overview of the role of alpha-synuclein in PD will be discussed with an emphasis on recent studies utilizing an immunization approach against alpha-synuclein as a possible treatment option for this debilitating disease.

There is of course a natural process that can be considered 140 amino acids replacement therapy. Amino Acid Therapy exists at

http://www.blog.parkinsonsrecovery.com/category/amino-acid-therapy/

Operational Definition for Tremor

A tremor is an involuntary,[1] somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the hands. In some people, a tremor is a symptom of another neurological disorder. A very common tremor is the chattering of teeth, usually induced by cold temperatures or by fear.

Causes

Tremor can be a symptom associated with disorders in those parts of the brain that control muscles throughout the body or in particular areas, such as the hands. Neurological disorders or conditions that can produce tremor including multiple sclerosis, stroke, traumatic brain injury, chronic kidney disease and a number of neurodegenerative diseases that damage or destroy parts of the brainstem or the cerebellum, Parkinson's disease being the one most often associated with tremor.

Other causes include the use of drugs (such as amphetamines, cocaine, caffeine, corticosteroids, SSRI), alcohol, mercury poisoning; or the withdrawal of drugs such as alcohol or benzodiazepine.

Tremors can also be seen in infants with phenylketonuria (PKU), overactive thyroid or liver failure. Tremors can be an indication of hypoglycemia, along with palpitations, sweating and anxiety. Tremor can also be caused from lack of sleep, lack of vitamins, or increased stress.[citation

needed]

Deficiencies of magnesium and thiamine have also been known to cause tremor or shaking, which resolves when the deficiency is corrected. See magnesium in biology. Some forms of tremor are inherited and run in families, while others have no known cause. Tremors can also be caused by some spider bites, e.g. the redback spider of Australia.

Characteristics may include a rhythmic shaking in the hands, arms, head, legs, or trunk; shaky voice; and problems holding things such as a fork or pen. Some tremors may be triggered by or become exacerbated during times of stress or strong emotion, when the individual is physically exhausted, or during certain postures or movements.

Tremor may occur at any age but is most common in middle-age and older persons. It may be occasional, temporary, or occur intermittently. Tremor affects men and women equally.

Types

Tremor is most commonly classified by clinical features and cause or origin. Some of the better known forms of tremor, with their symptoms, include the following:

Cerebellar tremor (also known as intention tremor) is a slow, broad tremor of the extremities that occurs at the end of a purposeful movement, such as trying to press a button or touching a finger to the tip of one’s nose. Cerebellar tremor is caused by lesions

in or damage to the cerebellum resulting from stroke, tumor, or disease such as multiple sclerosis or some inherited degenerative disorder. It can also result from chronic alcoholism or overuse of some medicines. In classic cerebellar tremor, a lesion on one side of the brain produces a tremor in that same side of the body that worsens with directed movement. Cerebellar damage can also produce a “wing-beating” type of tremor called rubral or Holmes’ tremor — a combination of rest, action, and postural tremors. The tremor is often most prominent when the affected person is active or is maintaining a particular posture. Cerebellar tremor may be accompanied by other manifestations of ataxia, including dysarthria (speech problems), nystagmus (rapid, involuntary rolling of the eyes), gait problems and postural tremor of the trunk and neck. Titubation is tremor of the head and is of cerebellar origin.

Dystonic tremor occurs in individuals of all ages who are affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive motions and/or painful and abnormal postures or positions. Dystonic tremor may affect any muscle in the body and is seen most often when the patient is in a certain position or moves a certain way. The pattern of dystonic tremor may differ from essential tremor. Dystonic tremors occur irregularly and often can be relieved by complete rest. Touching the affected body part or muscle may reduce tremor severity (a geste antagoniste). The tremor may be the initial sign of dystonia localized to a particular part of the body.

Essential tremor (sometimes called benign essential tremor) is the most common of the more than 20 types of tremor. Although the tremor may be mild and nonprogressive in some people, in others, the tremor is slowly progressive, starting on one side of the body but affecting both sides within 3 years. The hands are most often affected but the head, voice, tongue, legs, and trunk may also be involved. Head tremor may be seen as a “yes-yes” or “no-no” motion. Essential tremor may be accompanied by mild gait disturbance. Tremor frequency may decrease as the person ages, but the severity may increase, affecting the person’s ability to perform certain tasks or activities of daily living. Heightened emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and/or increase their severity. Onset is most common after age 40, although symptoms can appear at any age. It may occur in more than one family member. Children of a parent who has essential tremor have a 50 percent chance of inheriting the condition. Essential tremor is not associated with any known pathology.

Orthostatic tremor is characterized by fast (>12 Hz) rhythmic muscle contractions that occur in the legs and trunk immediately after standing. Cramps are felt in the thighs and legs and the patient may shake uncontrollably when asked to stand in one spot. No other clinical signs or symptoms are present and the shaking ceases when the patient sits or is lifted off the ground. The high frequency of the tremor often makes the tremor look like rippling of leg muscles while standing. Orthostatic tremor may also occur in patients who have essential tremor, and there might be an overlap between these categories of tremor.

Parkinsonian tremor is caused by damage to structures within the brain that control movement. This resting tremor, which can occur as an isolated symptom or be seen in other disorders, is often a precursor to Parkinson's disease (more than 25 percent of patients with Parkinson’s disease have an associated action tremor). The tremor, which is classically seen as a "pill-rolling" action of the hands that may also affect the chin, lips, legs, and trunk, can be markedly increased by stress or emotion. Onset is generally after

age 60. Movement starts in one limb or on one side of the body and usually progresses to include the other side.

Physiological tremor occurs in every normal individual and has no clinical significance. It is rarely visible and may be heightened by strong emotion (such as anxiety[2] or fear), physical exhaustion, hypoglycemia, hyperthyroidism, heavy metal poisoning, stimulants, alcohol withdrawal or fever. It can be seen in all voluntary muscle groups and can be detected by extending the arms and placing a piece of paper on top of the hands. Enhanced physiological tremor is a strengthening of physiological tremor to more visible levels. It is generally not caused by a neurological disease but by reaction to certain drugs, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia.

It is usually reversible once the cause is corrected. This tremor classically has a frequency of about 10 Hz [3]

Psychogenic tremor (also called hysterical tremor) can occur at rest or during postural or kinetic movement. The characteristics of this kind of tremor may vary but generally include sudden onset and remission, increased incidence with stress, change in tremor direction and/or body part affected, and greatly decreased or disappearing tremor activity when the patient is distracted. Many patients with psychogenic tremor have a conversion disorder (see Posttraumatic stress disorder) or another psychiatric disease.

Rubral tremor is characterized by coarse slow tremor which is present at rest, at posture and with intention. This tremor is associated with conditions which affect the red nucleus in the midbrain, classically unusual strokes.

Tremor can result from other conditions as well:

Alcoholism , excessive alcohol consumption, or alcohol withdrawal can kill certain nerve cells, resulting a tremor known as asterixis. Conversely, small amounts of alcohol may help to decrease familial and essential tremor, but the mechanism behind it is unknown. Alcohol potentiates GABAergic transmission and might act at the level of the inferior olive.

Tremor in peripheral neuropathy may occur when the nerves that supply the body’s muscles are traumatized by injury, disease, abnormality in the central nervous system, or as the result of systemic illnesses. Peripheral neuropathy can affect the whole body or certain areas, such as the hands, and may be progressive. Resulting sensory loss may be seen as a tremor or ataxia (inability to coordinate voluntary muscle movement) of the affected limbs and problems with gait and balance. Clinical characteristics may be similar to those seen in patients with essential tremor.

Tobacco withdrawal symptoms include tremor. Most of the symptoms can also occur randomly when panicked.

Diagnosis

During a physical exam a doctor can determine whether the tremor occurs primarily during action or at rest. The doctor will also check for tremor symmetry, any sensory loss, weakness or muscle atrophy, or decreased reflexes. A detailed family history may indicate if the tremor is inherited. Blood or urine tests can detect thyroid malfunction, other metabolic causes, and abnormal levels of certain chemicals that can cause tremor. These tests may also help to identify contributing causes, such as drug interaction, chronic alcoholism, or another condition or disease. Diagnostic imaging using CT or MRI imaging may help determine if the tremor is the result of a structural defect or degeneration of the brain.

The doctor will perform a neurological examination to assess nerve function and motor and sensory skills. The tests are designed to determine any functional limitations, such as difficulty with handwriting or the ability to hold a utensil or cup. The patient may be asked to place a finger on the tip of her or his nose, draw a spiral, or perform other tasks or exercises.

The doctor may order an electromyogram to diagnose muscle or nerve problems. This test measures involuntary muscle activity and muscle response to nerve stimulation. The selection of the sensors used is important. In addition to studies of muscle activity, tremor can be assessed with accuracy using accelerometers .[4]

Categories[edit]

The degree of tremor should be assessed in four positions. The tremor can then be classified by which position most accentuates the tremor:[5]

Position Name Description

At restResting tremors

Tremors that are worse at rest include Parkinsonian syndromes and essential tremor if severe. This includes drug-induced tremors from blockers of dopamine receptors such as haloperidol and other antipsychotic drugs.

During contraction (e.g. a tight fist while the arm is resting and supported)

Contraction tremors

Tremors that are worse during supported contraction include essential tremor and also cerebellar and exaggerated physiological tremors such as a hyperadrenergic state or hyperthyroidism.[5] Drugs such as adrenergics, anticholinergics, and xanthines can exaggerate physiological tremor.

During posture (e.g. with the arms elevated against gravity such as in a 'bird-wing' position)

Posture tremors

Tremors that are worse with posture against gravity include essential tremor and exaggerated physiological tremors.[5]

During intention (e.g. finger to nose test)

Intention tremors

Intention tremors are tremors that are worse during intention, e.g. as the patient's finger approaches a target, including cerebellar disorders. The terminology of "intention" is currently less used, to the profit of "kinetic".

Treatment

There is no cure for most tremors. The appropriate treatment depends on accurate diagnosis of the cause. Some tremors respond to treatment of the underlying condition. For example, in some cases of psychogenic tremor, treating the patient’s underlying psychological problem may cause the tremor to disappear. A few medications can help relieve symptoms temporarily.

Medications

Medications remain the basis of therapy in many cases. Symptomatic drug therapy is available for several forms of tremor:

Parkinsonian tremor drug treatment involves L-DOPA and/or dopamine-like drugs such as pergolide, bromocriptine and ropinirole; They can be dangerous, however, as they may cause symptoms such as tardive dyskinesia, akathisia, clonus, and in rare instances tardive (late developing) psychosis. Other drugs used to lessen parkinsonian tremor include amantadine and anticholinergic drugs like benzatropine

Essential tremor may be treated with beta blockers (such as propranolol and nadolol) or primidone, an anticonvulsant

Cerebellar tremor symptoms may decrease with the application of alcohol (ethanol) or benzodiazepine medications, both of which carry some risk of dependence and/or addiction

Rubral tremor patients may receive some relief using L-DOPA or anticholinergic drugs. Surgery may be helpful

Dystonic tremor may respond to diazepam, anticholinergic drugs, and intramuscular injections of botulinum toxin. Botulinum toxin is also prescribed to treat voice and head tremors and several movement disorders

Primary orthostatic tremor sometimes is treated with a combination of diazepam and primidone. Gabapentin provides relief in some cases

Enhanced physiological tremor is usually reversible once the cause is corrected. If symptomatic treatment is needed, beta blockers can be used (is there a natural beta blocker?)

Lifestyle[edit]

Eliminating tremor “triggers” such as caffeine and other stimulants from the diet is often recommended. Essential tremor may benefit from slight doses of ethanol, but the potential negative consequences of regular ethanol intake need to be taken into account. Beta blockers have been used as an alternative to alcohol in sports such as competitive dart playing and carry less potential for addiction.

Physical therapy may help to reduce tremor and improve coordination and muscle control for some patients. A physical therapist will evaluate the patient for tremor positioning, muscle control, muscle strength, and functional skills. Teaching the patient to brace the affected limb during the tremor or to hold an affected arm close to the body is sometimes useful in gaining motion control. Coordination and balancing exercises may help some patients. Some therapists

recommend the use of weights, splints, other adaptive equipment, and special plates and utensils for eating.

Surgery

Surgical intervention such as thalamotomy and deep brain stimulation may ease certain tremors. These surgeries are usually performed only when the tremor is severe and does not respond to drugs. Response can be excellent.

Thalamotomy, involving the creation of lesions in the brain region called the thalamus, is quite effective in treating patients with essential, cerebellar, or Parkinsonian tremor. This in-hospital procedure is performed under local anesthesia, with the patient awake. After the patient’s head is secured in a metal frame, the surgeon maps the patient’s brain to locate the thalamus. A small hole is drilled through the skull and a temperature-controlled electrode is inserted into the thalamus. A low-frequency current is passed through the electrode to activate the tremor and to confirm proper placement. Once the site has been confirmed, the electrode is heated to create a temporary lesion. Testing is done to examine speech, language, coordination, and tremor activation, if any. If no problems occur, the probe is again heated to create a 3-mm permanent lesion. The probe, when cooled to body temperature, is withdrawn and the skull hole is covered. The lesion causes the tremor to permanently disappear without disrupting sensory or motor control.

Deep brain stimulation (DBS) uses implantable electrodes to send high-frequency electrical signals to the thalamus. The electrodes are implanted as described above. The patient uses a hand-held magnet to turn on and turn off a pulse generator that is surgically implanted under the skin. The electrical stimulation temporarily disables the tremor and can be “reversed,” if necessary, by turning off the implanted electrode. Batteries in the generator last about 5 years and can be replaced surgically. DBS is currently used to treat parkinsonian tremor and essential tremor. It is also applied successfully for other rare causes of tremor.

The most common side effects of tremor surgery include dysarthria (problems with motor control of speech), temporary or permanent cognitive impairment (including visual and learning difficulties), and problems with balance.

Biomechanical loading

As well as medication, rehabilitation programmes and surgical interventions, the application of biomechanical loading on tremor movement has been shown to be a technique that is able to suppress the effects of tremor on the human body. It has been established in the literature that most of the different types of tremor respond to biomechanical loading. In particular, it has been clinically tested that the increase of damping and/or inertia in the upper limb leads to a reduction of the tremorous motion. Biomechanical loading relies on an external device that either passively or actively acts mechanically in parallel to the upper limb to counteract tremor movement. This phenomenon gives rise to the possibility of an orthotic management of tremor.

Starting from this principle, the development of upper-limb non-invasive ambulatory robotic exoskeletons is presented as a promising solution for patients who cannot benefit from medication to suppress the tremor. In this area robotic exoskeletons have emerged, in the form of orthoses, to provide motor assistance and functional compensation to disabled people. An orthosis is a wearable device that acts in parallel to the affected limb. In the case of tremor management, the orthosis must apply a damping or inertial load to a selected set of limb articulations.

Recently, some studies demonstrated that exoskeletons could achieve a consistent 40% of tremor power reduction for all users, being able to attain a reduction ratio in the order of 80% tremor power in specific joints of users with severe tremor.[6] In addition, the users reported that the exoskeleton did not affect their voluntary motion. These results indicate the feasibility of tremor suppression through biomechanical loading.

The main drawbacks of this mechanical management of tremor are (1) the resulting bulky solutions, (2) the inefficiency in transmitting loads from the exoskeleton to the human musculo-skeletal system and (3) technological limitations in terms of actuator technologies. In this regard, current trends in this field are focused on the evaluation of the concept of biomechanical loading of tremor through selective Functional Electrical Stimulation (FES) based on a (Brain-to-Computer Interaction) BCI-driven detection of involuntary (tremor) motor activity.[7]

See also

Chronic solvent-induced encephalopathy Fasciculation   These twitches of "at rest" skeletal muscle are too weak to cause any joint

movements, and fall short of the definition of a tremor. Usually benign, but also a symptom of some very serious neurological disorders such as ALS.

Neurology Shivering

References

1. Jump up ̂ "tremor" at Dorland's Medical Dictionary2. Jump up ̂ Allan H. Goroll; Albert G. Mulley (1 January 2009). Primary care medicine: office

evaluation and management of the adult patient. Lippincott Williams & Wilkins. p. 1178. ISBN 978-0-7817-7513-7. Retrieved 30 May 2011.

3. Jump up ̂ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC497216/pdf/jnnpsyc00292-0020.pdf4. Jump up ̂ Grimaldi G, Manto M. "Neurological tremor: sensors, signal processing and

emerging applications." Sensors. 2010;10:1399–14225. ^ Jump up to: a b c Jankovic J, Fahn S. Physiologic and pathologic tremors. Diags, mechanism, and

management. Ann Intern Med. 1980;93:460–465. PMID 70019676. Jump up ̂ Rocon E, Belda-Lois JM, Ruiz AF, Manto M, Moreno JC, Pons JL. "Design and

Validation of a Rehabilitation Robotic Exoskeleton for Tremor Assessment and Suppression." IEEE Transactions on Neural Systems and Rehabilitation Engineering. 2007;15(3):367–378

7. Jump up ̂ Tremor project   – ICT-2007-224051 [dead link]

External links

Wikimedia Commons has media related to Tremor.

"NINDS Tremor Information Page" . National Institute of Neurological Disorders and Stroke. July 20, 2007. Retrieved 2007-10-08. Some text copied with permission and thanks.

"Leonid L. Rubchinsky et al. (2007) Tremor. Scholarpedia 2(10):1379" . orthostatictremor.org

[show]

v

t

e

Pathology of the nervous system, primarily CNS (G04–G47, 323–349)

Brain

Encephalitis

o Viral encephalitis

o Herpesviral encephalitis

o Limbic encephalitis

o Encephalitis lethargica

Cavernous sinus thrombosis

Brain abscess

o Amoebic

o

Spinal cord

Myelitis : Poliomyelitis

Demyelinating disease

o Transverse myelitis

Tropical spastic paraparesis

Epidural abscess

Both/either Encephalomyelitis

o Acute disseminated

o Myalgic

Meningoencephalitis

Degenerative Extrapyramidal and

movement disorders

Basal ganglia disease

o Parkinsonism

PD

Postencephalitic

NMS

o PKAN

o Tauopathy

PSP

o Striatonigral

degeneration

o Hemiballismus

o HD

o OA

Dyskinesia

o Dystonia

Status

dystonicus

Spasmodic

torticollis

Meige's

Blepharospasm

o Athetosis

o Chorea

Choreoathetosis

o Myoclonus

Myoclonic

epilepsy

o Akathisia

Tremor

o Essential tremor

o Intention tremor

Restless legs

Stiff person

Dementia

Tauopathy

o Alzheimer's

Early-onset

o Primary progressive

aphasia

Frontotemporal

dementia/Frontotemporal lobar

degeneration

o Pick's

o Dementia with Lewy

bodies

Posterior cortical atrophy

Vascular dementia

Mitochondrial disease

Leigh's disease

Demyelinating autoimmune

o Multiple sclerosis

o Neuromyelitis optica

o Schilder's disease

hereditary

o Adrenoleukodystrophy

o Alexander

o Canavan

o Krabbe

o ML

o PMD

o VWM

o MFC

o CAMFAK syndrome

Central pontine myelinolysis

Marchiafava-Bignami disease

Alpers' disease

Episodic/

paroxysmal

Seizure/epilepsy

Focal

Generalised

Status epilepticus

Myoclonic epilepsy

Headache

Migraine

o Familial hemiplegic

Cluster

Tension

Cerebrovascular

TIA

o Amaurosis fugax

o Transient global amnesia

o Acute aphasia

Stroke

o MCA

o ACA

o PCA

o Foville's

o Millard-Gubler

o Lateral medullary

o Weber's

o Lacunar stroke

oSleep disorders Insomnia

Hypersomnia

Sleep apnea

o Obstructive

o Ondine's curse

Narcolepsy

Cataplexy

Kleine-Levin

Circadian rhythm sleep disorder

o Advanced sleep phase

disorder

o Delayed sleep phase disorder

o Non-24-hour sleep–wake

disorder

o Jet lag

CSF

Intracranial hypertension

o Hydrocephalus /NPH

o Choroid plexus papilloma

o Idiopathic intracranial hypertension

Cerebral edema

Intracranial hypotension

Other

Brain herniation

Reye's

Hepatic encephalopathy

Toxic encephalopathy

Hashimoto's encephalopathy

Degenerative

SA Friedreich's ataxia

Ataxia telangiectasia

MND UMN only:

o Primary lateral sclerosis

o Pseudobulbar palsy

o Hereditary spastic paraplegia

LMN only:

o Distal hereditary motor neuropathies

o Spinal muscular atrophies

SMA

SMAX1

SMAX2

DSMA1

Congenital DSMA

SMA-PCH

SMA-LED

SMA-PME

o Progressive muscular atrophy

o Progressive bulbar palsy

Fazio–Londe

Infantile progressive bulbar palsy

both:

o Amyotrophic lateral sclerosis

v

t

e

Index of the central nervous system

Description Anatomy

o meninges

o cortex

association fibers

commissural fibers

o lateral ventricles

o basal ganglia

o diencephalon

o mesencephalon

o pons

o cerebellum

o medulla

o spinal cord

tracts

Physiology

o neutrotransmission

enzymes

intermediates

Development

Disease

Cerebral palsy

Meningitis

Demyelinating diseases

Seizures and epilepsy

Headache

Stroke

Sleep

Congenital

Injury

Neoplasms and cancer

Other

o paralytic syndromes

o ALS

Symptoms and signs

o head and neck

o eponymous

o lesions

Tests

o CSF

oTreatment Procedures

Drugs

o general anesthetics

o analgesics

o addiction

o epilepsy

o cholinergics

o migraine

o Parkinson's

o vertigo

o other

[show]

v

t

e

Symptoms and signs: nervous and musculoskeletal systems (R25–R29, 781.0, 781.2–9)

Primarily CNS

Movement disorders

Dyskinesia : Athetosis

Tremor

Dyskinesia

Gait abnormality

Scissor gait

Cerebellar ataxia

Festinating gait

Marche a petit pas

Propulsive gait

Stomping gait

Spastic gait

Magnetic gait

Lack of coordination Dyskinesia : Ataxia

o Cerebellar

ataxia/Dysmetria

o Sensory ataxia

o Dyssynergia

Dysdiadochokinesia

Asterixis

Other

Abnormal posturing :

Opisthotonus

Sensory processing

disorder: Hemispatial

neglect

Facial weakness

Hyperreflexia

Pronator drift

Primarily PNS Gait abnormality Steppage gait

Antalgic gait

Movement disorders

Spasm

o Trismus

Fasciculation

Fibrillation

Myokymia

Cramp

Gait abnormality

Myopathic gait

Trendelenburg gait

Pigeon gait

Other Tetany

Meningism

[show] 

Further indexes

v

t

e

Index of the central nervous system

Description

Anatomy

o meninges

o cortex

association fibers

commissural fibers

o lateral ventricles

o basal ganglia

o diencephalon

o mesencephalon

o pons

o cerebellum

o medulla

o spinal cord

tracts

Physiology

o neutrotransmission

enzymes

intermediates

Development

Disease Cerebral palsy

Meningitis

Demyelinating diseases

Seizures and epilepsy

Headache

Stroke

Sleep

Congenital

Injury

Neoplasms and cancer

Other

o paralytic syndromes

o ALS

Symptoms and signs

o head and neck

o eponymous

o lesions

Tests

o CSF

o

Treatment

Procedures

Drugs

o general anesthetics

o analgesics

o addiction

o epilepsy

o cholinergics

o migraine

o Parkinson's

o vertigo

o other

v

t

e

Index of the peripheral nervous system

Description Anatomy

Nerves

o cranial

o trigeminal

o cervical

o brachial

o lumbosacral plexus

o somatosensory

o spinal

o autonomic

Physiology

o reflexes

o proteins

o neurotransmitters

o transporters

Development

o neurotrophins

o

Disease

Autonomic

Congenital

Injury

Neoplasms and cancer

Other

Symptoms and signs

o eponymous

o

Treatment Procedures

Local anesthetics

v

t

e

Index of muscle

Description Anatomy

o head

o neck

o arms

o chest and back

o diaphragm

o abdomen

o genital area

o legs

Muscle tissue

Physiology

o connective tissue

o

Disease

Myopathy

Soft tissue

Connective tissue

Congenital

o abdomen

o muscular dystrophy

Neoplasms and cancer

Injury

Symptoms and signs

o eponymous

o

Treatment

Procedures

Drugs

o anti-inflammatory

o muscle relaxants

v

t

e

Index of bones and cartilage

Description Anatomy

o bones

o skull

face

neurocranium

compound structures

foramina

o upper extremity

o torso

o pelvis

o lower extremity

Physiology

Development

Cells

Disease

Congenital

Neoplasms and cancer

Trauma

o fracture

Other

Symptoms and signs

o eponymous

o

Treatment

Procedures

Drugs

Surgery

o approaches

v

t

e

Index of joint

Description Anatomy

o head and neck

o cranial

o arms

o torso and pelvis

o legs

o bursae and sheathes

Physiology

Disease

Arthritis

o acquired

o back

o childhood

o soft tissue

Congenital

Injury

Symptoms and signs

o eponymous

o orthopaedic

Examination

Treatment

Procedures

Drugs

o rheumatoid arthritis

o gout

o topical analgesics

<img src="//en.wikipedia.org/wiki/Special:CentralAutoLogin/start?type=1x1" alt="" title="" width="1" height="1" style="border: none; position: absolute;" />Retrieved from "https://en.wikipedia.org/w/index.php?title=Tremor&oldid=670022408" Categories:

Symptoms and signs: Nervous system

Essential tremor disorder affects about 14 percent of individuals 65 and over. Although half of these cases occur because of a genetic mutation (familial tremor), it is unknown what contributes to the disorder in people without this mutation. Currently, there is no cure for essential tremor disorder, but therapies may include physical therapy, beta-blockers, or anti-convulsant drugs. In other cases, it may be helpful to eliminate stimulants from the diet, i.e., caffeine.

What may be more concerning is that your friend is smoking weed (aka marijuana, pot) everyday. Individuals who smoke weed may become addicted, which means that they need more and more of the drug to get the same "high." The American Academy of Family Physicians

mentions that marijuana use may actually cause tremors (shaking) and decreased coordination, along with the following common side effects:

Trouble remembering things Slowed reaction time Difficulty concentrating Sleepiness Anxiety Paranoia (feeling that people are "out to get you") Altered time perception Red, bloodshot eyes

Moreover, marijuana may also have long-term health effects on the lungs — emerging research shows that smoking pot may even be associated with cancer. You may want to consider having a talk with your friend about why she smokes and whether she believes she is gaining anything from her marijuana use. While you can't force her to quit, you can express your concern and point out that the marijuana may be contributing to her tremors. If your friend is a student at Columbia and would like to speak with a health care provider about her tremors or her smoking, she can make an appointment by calling x4-2284 or visiting Open Communicator. She can also see any provider from Counseling and Psychological Services by calling x4-2878 to make an appointment.

For more resources, check out Wants to stop smoking pot in the Go Ask Alice! alcohol and other drugs archives. What your friend is dealing with is no small matter, but she is certainly fortunate to have a concerned and supportive friend like yourself.

Good luck,

Beta blockers (β-blockers, beta-adrenergic blocking agents, beta antagonists, beta-adrenergic antagonists, beta-adrenoreceptor antagonists, or beta adrenergic receptor antagonists) are a class of drugs that are particularly used for the management of cardiac arrhythmias, protecting the heart from a second heart attack (myocardial infarction) after a first heart attack (secondary prevention),[1] and, in certain cases, hypertension.[2][3]

Beta blockers block the action of endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) -in particular on adrenergic beta receptors, of the sympathetic nervous system, which mediates the fight-or-flight response.[4][5] Some block all activation of β-adrenergic receptors and others are selective.

Three types of beta receptors are known, designated β1, β2 and β3 receptors.[6] β1-adrenergic receptors are located mainly in the heart and in the kidneys.[5] β2-adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle.[5] β3-adrenergic receptors are located in fat cells.[7]

Beta receptors are found on cells of the heart muscles, smooth muscles, airways, arteries, kidneys, and other tissues that are part of the sympathetic nervous system and lead to stress

responses, especially when they are stimulated by epinephrine (adrenaline). Beta blockers interfere with the binding to the receptor of epinephrine and other stress hormones, and weaken the effects of stress hormones.

In 1964, Sir James W. Black [8] found the first clinically significant beta blockers—propranolol and pronethalol; it revolutionized the medical management of angina pectoris [9] and is considered by many to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.[10]

In comparison with other antihypertensive drugs, beta blockers are less than optimal for the treatment of primary hypertension, with a raised risk of stroke.[11]

Contents

 [hide] 

1 Medical uses o 1.1 Congestive heart failure o 1.2 Anxiety o 1.3 Surgery

2 Adverse effects o 2.1 Contraindications o 2.2 Toxicity

3 β-Receptor antagonism 4 Intrinsic sympathomimetic activity 5 α 1-Receptor antagonism 6 Other effects 7 Examples

o 7.1 Nonselective agents o 7.2 β 1-selective agentso 7.3 β 2-selective agentso 7.4 β 3-selective agents

8 Comparative information o 8.1 Pharmacological differences o 8.2 Indication differences

9 See also 10 References 11 External links

Medical uses[edit]

Large differences exist in the pharmacology of agents within the class, thus not all beta blockers are used for all indications listed below.

Indications for beta blockers include:

Angina pectoris [12] [13] Atrial fibrillation [14] Cardiac arrhythmia Congestive heart failure Essential tremor Glaucoma Hypertension Migraine prophylaxis Mitral valve prolapse Myocardial infarction Phaeochromocytoma , in conjunction with α-blocker Postural orthostatic tachycardia syndrome Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism Theophylline overdose

Beta blockers have also been used for:

Acute aortic dissection Hypertrophic obstructive cardiomyopathy Marfan syndrome (treatment with propranolol slows progression of aortic dilation and its

complications) Prevention of variceal bleeding in portal hypertension Possible mitigation of hyperhidrosis Social and other anxiety disorders Controversially, for reduction of perioperative mortality

Congestive heart failure[edit]

Although beta blockers were once contraindicated in congestive heart failure, as they have the potential to worsen the condition, studies in the late 1990s showed their efficacy at reducing morbidity and mortality.[15][16][17] Bisoprolol, carvedilol, and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE inhibitor and diuretic therapy in congestive heart failure.

Beta blockers are known primarily for their reductive effect on heart rate, although this is not the only mechanism of action of importance in congestive heart failure.[citation needed] Beta blockers, in addition to their sympatholytic B1 activity in the heart, influence the renin–angiotensin system at the kidneys. Beta blockers cause a decrease in renin secretion, which in turn reduces the heart oxygen demand by lowering extracellular volume and increasing the oxygen-carrying capacity of blood. Beta blockers' sympatholytic activities reduce heart rate, thereby increasing the ejection fraction of the heart despite an initial reduction in ejection fraction.

Trials have shown beta blockers reduce the absolute risk of death by 4.5% over a 13-month period. In addition to reducing the risk of mortality, the numbers of hospital visits and hospitalizations were also reduced in the trials.[18]

Anxiety[edit]

Officially, beta blockers are not approved for anxiolytic use by the U.S. Food and Drug Administration.[19] However, many controlled trials in the past 25 years indicate beta blockers are effective in anxiety disorders, though the mechanism of action is not known.[20] The physiological symptoms of the fight-or-flight response (pounding heart, cold/clammy hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand.

Musicians, public speakers, actors, and professional dancers have been known to use beta blockers to avoid performance anxiety, stage fright, and tremor during both auditions and public performances. The application to stage fright was first recognized in The Lancet in 1976, and by 1987, a survey conducted by the International Conference of Symphony Orchestra Musicians, representing the 51 largest orchestras in the United States, revealed 27% of its musicians had used beta blockers and 70% obtained them from friends, not physicians.[21] Beta blockers are inexpensive, said to be relatively safe, and on one hand, seem to improve musicians' performances on a technical level, while some, such as Barry Green, the author of "The Inner Game of Music" and Don Greene, a former Olympic diving coach who teaches Juilliard students to overcome their stage fright naturally, say the performances may be perceived as "soulless and inauthentic".[21]

Since they promote lower heart rates and reduce tremors, beta blockers have been used in professional sports where high accuracy is required, including archery, shooting, golf [22] and snooker.[22] Beta blockers are banned by the International Olympic Committee.[23] A recent, high-profile transgression took place in the 2008 Summer Olympics, where 50- metre pistol silver medallist and 10-metre air pistol bronze medallist Kim Jong-su tested positive for propranolol and was stripped of his medals.

For similar reasons, beta blockers have also been used by stutterers[citation needed] and surgeons.[24]

Surgery[edit]

The use of beta blockers around the time of cardiac surgery decreases the risk of heart dysrhythmias.[25] Starting them around the time of other types of surgery, however, worsens outcomes.[25]

Adverse effects[edit]

Adverse drug reactions associated with the use of beta blockers include: nausea, diarrhea, bronchospasm, dyspnea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, heart failure, heart block, fatigue, dizziness, alopecia (hair loss), abnormal vision, hallucinations, insomnia, nightmares, sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism. Mixed α1/β-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with edema.[26] Due to the high penetration across the blood–brain barrier, lipophilic beta blockers, such as propranolol

and metoprolol, are more likely than other, less lipophilic, beta blockers to cause sleep disturbances, such as insomnia, vivid dreams and nightmares.[27]

Adverse effects associated with β2-adrenergic receptor antagonist activity (bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common with β1-selective (often termed "cardioselective") agents, but receptor selectivity diminishes at higher doses. Beta blockade, especially of the beta-1 receptor at the macula densa, inhibits renin release, thus decreasing the release of aldosterone. This causes hyponatremia and hyperkalemia.

Hypoglycemia can occur with beta blockade because β2-adrenoceptors normally stimulate hepatic glycogen breakdown (glycogenolysis) and pancreatic release of glucagon, which work together to increase plasma glucose. Therefore, blocking β2-adrenoceptors lowers plasma glucose. β1-blockers have fewer metabolic side effects in diabetic patients; however, the tachycardia that serves as a warning sign for insulin-induced hypoglycemia may be masked. Therefore, beta blockers are to be used cautiously in diabetics.[28]

A 2007 study revealed diuretics and beta blockers used for hypertension increase a patient's risk of developing diabetes, while ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers) actually decrease the risk of diabetes.[29] Clinical guidelines in Great Britain, but not in the United States, call for avoiding diuretics and beta blockers as first-line treatment of hypertension due to the risk of diabetes.[30]

Beta blockers must not be used in the treatment of cocaine, amphetamine, or other alpha-adrenergic stimulant overdose. The blockade of only beta receptors increases hypertension, reduces coronary blood flow, left ventricular function, and cardiac output and tissue perfusion by means of leaving the alpha-adrenergic system stimulation unopposed.[citation needed] The appropriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant abuse are vasodilators such as nitroglycerin, diuretics such as furosemide, and alpha blockers such as phentolamine.[31]

Contraindications[edit]

Beta blockers are contraindicated in patients with asthma as stated in the British National Formulary 2011.[citation needed] They should also be avoided in patients with a history of cocaine use or in cocaine-induced tachycardia.[citation needed]

Beta blockers should not be used as a first-line treatment in the acute setting for cocaine-induced acute coronary syndrome (CIACS). No recent studies have been identified that show the benefit of beta blockers in reducing coronary vasospasm, or coronary vascular resistance, in patients with CIACS. In the multiple case studies identified, the use of beta blockers in CIACS resulted in detrimental outcomes, and the discontinuation of beta blockers used in the acute setting led to improvement in clinical course.[citation needed] The guidelines by the American College of Cardiology/American Heart Association also support this idea, and recommend against the use of beta blockers in cocaine-induced ST-segment elevation myocardial infarction (MI) because of the risk of coronary vasospasm.[citation needed] Though, in general, beta blockers improve mortality in patients who have suffered MI, it is unclear whether patients with CIACS will benefit from this

mortality reduction because no studies assess the use of beta blockers in the long term, and because cocaine users may be prone to continue to abuse the substance, thus complicating the effect of drug therapy.[32]

Toxicity[edit]

Glucagon, used in the treatment of overdose,[33][34] increases the strength of heart contractions, increases intracellular cAMP, and decreases renal vascular resistance. It is, therefore, useful in patients with beta-blocker cardiotoxicity.[35][36] Cardiac pacing is usually reserved for patients unresponsive to pharmacological therapy.

Patients experiencing bronchospasm due to the β2 receptor-blocking effects of nonselective beta blockers may be treated with anticholinergic drugs, such as ipratropium, which are safer than beta agonists in patients with cardiovascular disease. Other antidotes for beta-blocker poisoning are salbutamol and isoprenaline.

β-Receptor antagonism[edit]

Stimulation of β1 receptors by epinephrine and norepinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity.[37] Stimulation of β1 receptors on the kidney causes renin release.[38] Stimulation of β2 receptors induces smooth muscle relaxation,[39] induces tremor in skeletal muscle,[40] and increases glycogenolysis in the liver and skeletal muscle.[41] Stimulation of β3 receptors induces lipolysis.[42]

Beta blockers inhibit these normal epinephrine- and norepinephrine-mediated sympathetic actions,[4] but have minimal effect on resting subjects.[citation needed] That is, they reduce excitement/physical exertion on heart rate and force of contraction,[43] and also tremor[44] and breakdown of glycogen, but increase dilation of blood vessels[45] and constriction of bronchi.[46]

Therefore, nonselective beta blockers are expected to have antihypertensive effects.[47] The primary antihypertensive mechanism of beta blockers is unclear, but may involve reduction in cardiac output (due to negative chronotropic and inotropic effects).[48] It may also be due to reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activity (for those beta blockers that do cross the blood–brain barrier, e.g. propranolol).

Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand. Negative chronotropic properties of beta blockers allow the lifesaving property of heart rate control. Beta blockers are readily titrated to optimal rate control in many pathologic states.

The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade—resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory periods. Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade.

Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin-angiotensin-aldosterone system, with a resultant decrease in blood pressure due to decreased sodium and water retention.

Intrinsic sympathomimetic activity[edit]

Also referred to as intrinsic sympathomimetic effect, this term is used particularly with beta blockers that can show both agonism and antagonism at a given beta receptor, depending on the concentration of the agent (beta blocker) and the concentration of the antagonized agent (usually an endogenous compound, such as norepinephrine). See partial agonist for a more general description.

Some beta blockers (e.g. oxprenolol, pindolol, penbutolol, and acebutolol) exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of exerting low-level agonist activity at the β-adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be useful in individuals exhibiting excessive bradycardia with sustained beta blocker therapy.

Agents with ISA are not used after myocardial infarctions, as they have not been demonstrated to be beneficial. They may also be less effective than other beta blockers in the management of angina and tachyarrhythmia.[26]

α1-Receptor antagonism[edit]

Some beta blockers (e.g., labetalol and carvedilol) exhibit mixed antagonism of both β- and α1-adrenergic receptors, which provides additional arteriolar vasodilating action.

Other effects[edit]

Beta blockers decrease nocturnal melatonin release, perhaps partly accounting for sleep disturbances caused by some agents.[49]

They can also be used to treat glaucoma because they decrease intraocular pressure by lowering aqueous humor secretion.[50]

Examples[edit]

Dichloroisoprenaline, the first beta blocker

Nonselective agents[edit]

Propranolol Bucindolol Carteolol Carvedilol (has additional α-blocking activity) Labetalol (has additional α-blocking activity) Nadolol Oxprenolol (has intrinsic sympathomimetic activity) Penbutolol (has intrinsic sympathomimetic activity) Pindolol (has intrinsic sympathomimetic activity) Sotalol Timolol Eucommia bark (herb) [51]

β1-selective agents[edit]

Also known as cardioselective

Acebutolol (has intrinsic sympathomimetic activity) Atenolol Betaxolol Bisoprolol Celiprolol Esmolol [52] Metoprolol Nebivolol (also increases nitric oxide release for vasodilation)

β2-selective agents[edit]

Butaxamine (weak α-adrenergic agonist activity): No common clinical applications, but used in experiments

ICI-118,551 : Highly selective β2-adrenergic receptor antagonist—no known clinical applications, but used in experiments due to its strong receptor specificity

β3-selective agents[edit]

SR 59230A (has additional α-blocking activity): Used in experiments

Comparative information[edit]

Pharmacological differences[edit]

Agents with intrinsic sympathomimetic action (ISA) o Acebutolol, carteolol, celiprolol, mepindolol, oxprenolol, pindolol

Agents with greater aqueous solubility (hydrophilic beta blockers) o Atenolol, celiprolol, nadolol, sotalol

Agents with membrane stabilizing effect o Acebutolol, propranolol

Indication differences[edit]

Agents specifically indicated for cardiac arrhythmia o Esmolol , sotalol, landiolol

Agents specifically indicated for congestive heart failure o carvedilol , sustained-release metoprolol, bisoprolol,

Agents specifically indicated for glaucoma o Betaxolol , carteolol, levobunolol, metipranolol, timolol

Agents specifically indicated for myocardial infarction o Atenolol , metoprolol, propranolol

Agents specifically indicated for migraine prophylaxis o Timolol , propranolol

Propranolol is the only agent indicated for control of tremor, portal hypertension, and esophageal variceal bleeding, and used in conjunction with α-blocker therapy in phaeochromocytoma.[26]

See also[edit]

Alpha blockers

References[edit]

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External links[edit]

Musicians and beta-blockers by Gerald Klickstein, March 11, 2010 (A blog post that considers "whether beta-blockers are safe, effective, and appropriate for performers to use.")

Better Playing Through Chemistry by Blair Tindall, New York Times, October 17, 2004. (Discusses the use of beta blockers among professional musicians)

Musicians using beta blockers by Blair Tindall. Condensed version of above article. In Defense of the Beta Blocker by Carl Elliott, The Atlantic, August 20, 2008. (Discusses

the use of propranolol by a North Korean pistol shooter in the 2008 Olympics) beta-Adrenergic Blockers at the US National Library of Medicine Medical Subject

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t

e

Index of the circulatory system

Description Anatomy

Arteries

o head and neck

o arms

o chest

o abdomen

o legs

Veins

o head and neck

o arms

o chest

o abdomen and pelvis

o legs

Development

Cells

Physiology

o proteins

o

Disease

Congenital

Neoplasms and cancer

Lymphatic vessels

Injury

Vasculitis

Other

Symptoms and signs

o eponymous

o

Treatment

Procedures

Drugs

o beta blockers

o channel blockers

o diuretics

o nonsympatholytic vasodilatory antihypertensives

o peripheral vasodilators

o renin–angiotensin system

o sympatholytic antihypertensives

o vasoprotectives

[show]

v

t

e

Pharmacology: major drug groups

[show]

v

t

e

Sympatholytic (and closely related) antihypertensives (C02)

Central

α2 agonist

Clonidine

Guanabenz

Guanfacine

Methyldopa #

Adrenergic release inhibitors

Bethanidine

Bretylium

Debrisoquine

Guanadrel

Guanazodine

Guanethidine

Guanoclor

Guanazodine

Guanoxabenz

Guanoxan

Imidazoline receptor agonist Moxonidine

Rilmenidine

Ganglion-blocking/nicotinic antagonist

Mecamylamine

Pentolinium

Trimethaphan

Periphera

l

Indirec

t

MAOI Pargyline ‡

Adrenergic uptake inhibitor

Bietaserpine

Deserpidine

Methoserpidin

e

Rescinnamine

Reserpine

Tyrosine hydroxylase

inhibitor Metirosine

Direct

α1 blockers

Prazosin

Indoramin

Trimazosin

Doxazosin

Urapidil

Non-selective α blocker

Phentolamine

Serotonin antagonist Ketanserin

Lidanserin

Endothelin antagonist (for PH) dual (Bosentan, Macitentan)

selective (Ambrisentan, Sitaxentan)

#WHO-EM

‡Withdrawn from market

Clinical trials :

o †Phase III

o §Never to phase III

v

t

e

Index of the circulatory system

Description

Anatomy

Arteries

o head and neck

o arms

o chest

o abdomen

o legs

Veins

o head and neck

o arms

o chest

o abdomen and pelvis

o legs

Development

Cells

Physiology

o proteins

o

Disease

Congenital

Neoplasms and cancer

Lymphatic vessels

Injury

Vasculitis

Other

Symptoms and signs

o eponymous

oTreatment Procedures

Drugs

o beta blockers

o channel blockers

o diuretics

o nonsympatholytic vasodilatory antihypertensives

o peripheral vasodilators

o renin–angiotensin system

o sympatholytic antihypertensives

o vasoprotectives

[show]

v

t

e

Drugs used for glaucoma preparations and miosis (S01E)

muscarinic Aceclidine

Pilocarpine

muscarinic/nicotinic Acetylcholine

Carbachol

Acetylcholinesterase inhibitors

Demecarium

Ecothiopate

Stigmine (Fluostigmine

Neostigmine

Physostigmine )

Paraoxon

v

t

e

Index of the eye

Description

Anatomy

o orbit

o neural pathways

Physiology

o Phenomena

appearance

visual

optical illusions

o proteins

Development

Disease

Congenital

Corneal dystrophy

Neoplasms and cancer

Other

Symptoms and signs

Treatment

Procedures

Drugs

o infection

o glaucoma and miosis

o mydriatics

o vascular

[show]

v

t

e

Adrenergics

[show] 

Receptor ligands

α1 Agonists

6-FNE

Amidephrine

Anisodamine

Anisodine

Buspirone

Cirazoline

Corbadrine

Dipivefrine

Dopamine

Ephedrine

Epinephrine

Etilefrine

Ethylnorepinephrine

Indanidine

Metaraminol

Methoxamine

Methyldopa

Midodrine

Naphazoline

Norepinephrine

Octopamine

Oxymetazoline

Phenylephrine

Phenylpropanolamine

Pseudoephedrine

Synephrine

Tetrahydrozoline

Antagonists

Abanoquil

Adimolol

Ajmalicine

Alfuzosin

Amosulalol

Arotinolol

Atiprosin

Atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, risperidone)

Benoxathian

Buflomedil

Bunazosin

Carvedilol

Corynanthine

Dapiprazole

Domesticine

Doxazosin

Ergolines (e.g., ergotamine, dihydroergotamine, lisuride, terguride)

Etoperidone

Eugenodilol

Fenspiride

Hydroxyzine

Indoramin

Ketanserin

L-765,314

Labetalol

mCPP

Mepiprazole

Metazosin

Monatepil

Moxisylyte

Naftopidil

Nantenine

Nefazodone

Neldazosin

Niaprazine

Nicergoline

Niguldipine

Pardoprunox

Pelanserin

Phendioxan

Phenoxybenzamine

Phentolamine

Piperoxan

Prazosin

Quinazosin

Ritanserin

Silodosin

Spiperone

Talipexole

Tamsulosin

Terazosin

Tiodazosin

Tolazoline

Trazodone

Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin)

Tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin,

imipramine, trimipramine)

Trimazosin

Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine,

thioridazine)

Urapidil

WB-4101

Zolertine

α2 Agonists

(R)-3-Nitrobiphenyline

4-NEMD

6-FNE

Amitraz

Apraclonidine

Brimonidine

Cannabivarin

Clonidine

Corbadrine

Detomidine

Dexmedetomidine

Dihydroergotamine

Dipivefrine

Dopamine

Ephedrine

Ergotamine

Epinephrine

Etilefrine

Ethylnorepinephrine

Guanabenz

Guanfacine

Guanoxabenz

Lofexidine

Medetomidine

Methamphetamine

Methyldopa

Mivazerol

Naphazoline

Norepinephrine

Oxymetazoline

Phenylpropanolamine

Piperoxan

Pseudoephedrine

Rilmenidine

Romifidine

Talipexole

Tetrahydrozoline

Tizanidine

Tolonidine

Urapidil

Xylazine

Xylometazoline

Antagonists

1-PP

Adimolol

Aptazapine

Atipamezole

Atypical antipsychotics (e.g., asenapine, clozapine, lurasidone, paliperidone,

quetiapine, risperidone, zotepine)

Azapirones (e.g., buspirone, tandospirone)

BRL-44408

Buflomedil

Cirazoline

Efaroxan

Esmirtazapine

Fenmetozole

Fluparoxan

Idazoxan

mCPP

Mianserin

Mirtazapine

NAN-190

Olanzapine

Pardoprunox

Phentolamine

Phenoxybenzamine

Piperoxan

Piribedil

Rauwolscine

Rotigotine

SB-269970

Setiptiline

Spiroxatrine

Sunepitron

Tolazoline

Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine,

thioridazine)

Yohimbine

β Agonists

Amibegron

Arbutamine

Arformoterol

Arotinolol

BAAM

Bambuterol

Befunolol

Bitolterol

Broxaterol

Buphenine

Carbuterol

Cimaterol

Clenbuterol

Corbadrine

Denopamine

Dipivefrine

Dobutamine

Dopamine

Dopexamine

Ephedrine

Epinephrine

Etafedrine

Etilefrine

Ethylnorepinephrine

Fenoterol

Formoterol

Hexoprenaline

Higenamine

Indacaterol

Isoetarine

Isoprenaline

Isoxsuprine

Levosalbutamol

Mabuterol

Methoxyphenamine

Methyldopa

Mirabegron

Norepinephrine

Orciprenaline

Oxyfedrine

Phenylpropanolamine

Pirbuterol

Prenalterol

Ractopamine

Procaterol

Pseudoephedrine

Reproterol

Rimiterol

Ritodrine

Salbutamol

Salmeterol

Solabegron

Terbutaline

Tretoquinol

Tulobuterol

Vilanterol

Xamoterol

Zilpaterol

Zinterol

Antagonists

Acebutolol

Adaprolol

Adimolol

Afurolol

Alprenolol

Alprenoxime

Amosulalol

Ancarolol

Arnolol

Arotinolol

Atenolol

Befunolol

Betaxolol

Bevantolol

Bisoprolol

Bopindolol

Bornaprolol

Brefonalol

Bucindolol

Bucumolol

Bufetolol

Bufuralol

Bunitrolol

Bunolol

Bupranolol

Butaxamine

Butidrine

Butofilolol

Capsinolol

Carazolol

Carpindolol

Carteolol

Carvedilol

Celiprolol

Cetamolol

Cicloprolol

Cinamolol

Cloranolol

Cyanopindolol

Dalbraminol

Dexpropranolol

Diacetolol

Dichloroisoprenaline

Dihydroalprenolol

Dilevalol

Diprafenone

Draquinolol

Ecastolol

Epanolol

Ericolol

Ersentilide

Esatenolol

Esprolol

Eugenodilol

Exaprolol

Falintolol

Flestolol

Flusoxolol

Hydroxycarteolol

Hydroxytertatolol

ICI-118,551

Idropranolol

Indenolol

Indopanolol

Iodocyanopindolol

Iprocrolol

Isoxaprolol

Isamoltane

Labetalol

Landiolol

Levobetaxolol

Levobunolol

Levomoprolol

Medroxalol

Mepindolol

Metipranolol

Metoprolol

Moprolol

Nadolol

Nadoxolol

Nebivolol

Nifenalol

Nipradilol

Oxprenolol

Pacrinolol

Pafenolol

Pamatolol

Pargolol

Penbutolol

Pindolol

Practolol

Primidolol

Procinolol

Pronethalol

Propafenone

Propranolol

Ridazolol

Ronactolol

Soquinolol

Sotalol

Spirendolol

SR 59230A

Sulfinalol

Talinolol

Tazolol

Tertatolol

Tienoxolol

Tilisolol

Timolol

Tiprenolol

Tolamolol

Toliprolol

Xibenolol

Xipranolol

[show] 

Reuptake inhibitors

NET Selective norepinephrine reuptake inhibitors

Amedalin

Atomoxetine (tomoxetine)

Ciclazindol

Daledalin

Edivoxetine

Esreboxetine

Lortalamine

Mazindol

Nisoxetine

Reboxetine

Talopram

Talsupram

Tandamine

Viloxazine

Norepinephrine-dopamine reuptake inhibitors

Amineptine

Bupropion

Fencamine

Fencamfamine

Hydroxybupropion

Lefetamine

Levophacetoperane

LR-5182

Manifaxine

Methylphenidate

Nomifensine

O-2172

Radafaxine

Serotonin-norepinephrine reuptake inhibitors

Bicifadine

Desvenlafaxine

Duloxetine

Eclanamine

Levomilnacipran

Milnacipran

N-Methyl-PPPA

PPPA

Sibutramine

Venlafaxine

Serotonin-norepinephrine-dopamine reuptake inhibitors

Brasofensine

Dasotraline

Desmethylsertraline

Diclofensine

DOV-102,677

DOV-21,947

DOV-216,303

HDMP-28

JNJ-7925476

JZ-IV-10

Liafensine

Naphyrone

NS-2359

Perafensine

PRC200

Tesofensine

Tricyclic antidepressants

Amitriptyline

Butriptyline

Cianopramine

Clomipramine

Desipramine

Dosulepin

Doxepin

Imipramine

Lofepramine

Melitracen

Nortriptyline

Protriptyline

Trimipramine

Tetracyclic antidepressants

Amoxapine

Maprotiline

Mianserin

Oxaprotiline

Setiptiline

Others

Antihistamines (e.g., brompheniramine, chlorphenamine, pheniramine,

tripelennamine)

Arylcyclohexylamines (e.g., ketamine, phencyclidine)

CP-39,332

Ethanol

EXP-561

Fezolamine

Ginkgo biloba

Indeloxazine

Loxapine

Nefazodone

Nefopam

Opioids (e.g., methadone, pethidine (meperidine), tapentadol, tramadol)

Pridefine

Tedatioxetine

Teniloxazine

Tofenacin

Tropanes (e.g., cocaine)

Ziprasidone

VMATs Amiodarone

Amphetamines (e.g., amphetamine, methamphetamine, MDMA)

Bietaserpine

Deserpidine

Efavirenz

GBR-12935

Ibogaine

Ketanserin

Lobeline

Reserpine

Rose bengal

Tetrabenazine

Vanoxerine (GBR-12909)

[show] 

Releasing agents

Morpholines

Fenbutrazate

Fenmetramide

Morazone

Morforex

Phendimetrazine

Phenmetrazine

Pseudophenmetrazine

Oxazolines

4-MAR

Aminorex

Clominorex

Cyclazodone

Fenozolone

Fluminorex

Pemoline

Thozalinone

Phenethylamines (also amphetamines, cathinones, etc)

2-OH-PEA

4-CAB

4-FA

4-FMA

4-MA

4-MMA

Alfetamine

Amfecloral

Amfepentorex

Amfepramone

Amphetamine

Dextroamphetamine

Levoamphetamine

Amphetaminil

β-Me-PEA

BDB

Benzphetamine

BOH

Buphedrone

Bupropion

Butylone

Cathine

Cathinone

Clobenzorex

Clortermine

Dimethylamphetamine

DMA

DMMA

EBDB

Ephedrine

Ethcathinone

Ethylone

Etilamfetamine

Famprofazone

Fenethylline

Fenproporex

Flephedrone

Fludorex

Furfenorex

Hordenine

4-Hydroxyamphetamine

5-APDI (IAP)

5-MAPDI (IMP)

Iofetamine (123I)

Lisdexamfetamine

Lophophine

MBDB

MDA

MDEA

MDMA

Metamfepramone

MDMPEA

MDOH

MDPEA

Mefenorex

Mephedrone

Mephentermine

Methamphetamine

Dextromethamphetamine

Levomethamphetamine

Methcathinone

Methedrone

Methylone

Morforex

Naphthylaminopropane

Ortetamine

p BA

p CA

Pentorex

Phenethylamine

Pholedrine

Phenpromethamine

Phentermine

Phenylpropanolamine

p IA

Prenylamine

Propylamphetamine

Pseudoephedrine

Selegiline (also D -Deprenyl )

Tiflorex

Tyramine

Xylopropamine

Zylofuramine

Piperazines

2C-B-BZP

BZP

MBZP

mCPP

MDBZP

MeOPP

pFPP

Others

2-ADN

2-AI

2-AT

2-BP

4-BP

5-IAI

Clofenciclan

Cyclopentamine

Cypenamine

Cyprodenate

Feprosidnine

Gilutensin

Heptaminol

Hexacyclonate

Indanorex

Isometheptene

Methylhexanamine

Octodrine

Phthalimidopropiophenone

Propylhexedrine (Levopropylhexedrine)

Tuaminoheptane

[show] 

Enzyme inhibitors

PAH 3,4-Dihydroxystyrene

TH

3-Iodotyrosine

Aquayamycin

Bulbocapnine

Metirosine

Oudenone

AAAD

Benserazide

Carbidopa

DFMD

Genistein

Methyldopa

DBH

Bupicomide

Disulfiram

Dopastin

Fusaric acid

Nepicastat

Phenopicolinic acid

Tropolone

PNMT

CGS-19281A

SKF-64139

SKF-7698

MAO Nonselective

Benmoxin

Caroxazone

Echinopsidine

Furazolidone

Hydralazine

Indantadol

Iproclozide

Iproniazid

Isocarboxazid

Isoniazid

Linezolid

Mebanazine

Metfendrazine

Nialamide

Octamoxin

Paraxazone

Phenelzine

Pheniprazine

Phenoxypropazine

Pivhydrazine

Procarbazine

Safrazine

Tranylcypromine

MAO-A selective

Amiflamine

Bazinaprine

Befloxatone

Brofaromine

Cimoxatone

Clorgiline

CX157 (Tyrima)

Eprobemide

Esuprone

Harmala alkaloids

Harmine

Harmaline

Tetrahydroharmine

Harman

Methylene blue

Metralindole

Minaprine

Moclobemide

Pirlindole

Sercloremine

Tetrindole

Toloxatone

MAO-B selective

Ladostigil

Lazabemide

Milacemide

Mofegiline

Pargyline

Rasagiline

Safinamide

Selegiline (also D -Deprenyl )

COMT

Entacapone

Nitecapone

Tolcapone

[show] 

Others

Precursors

L-Phenylalanine → L-Tyrosine → L-DOPA (Levodopa) →

Dopamine

L-DOPS (Droxidopa)

Cofactors Ferrous Iron (Fe2+)

S-Adenosyl-L-Methionine

Vitamin B 3 (Niacin

Nicotinamide → NADPH)

Vitamin B 6 (Pyridoxine

Pyridoxamine

Pyridoxal → Pyridoxal Phosphate)

Vitamin B 9 (Folic acid → Tetrahydrofolic acid)

Vitamin C (Ascorbic acid)

Zinc (Zn2+)

Neurotoxins DSP-4

Oxidopamine (6-OHDA)

Others

Activity enhancers

BPAP

PPAP

Release blockers

Bethanidine

Bretylium

Guanadrel

Guanazodine

Guanethidine

Guanoxan

<img src="//en.wikipedia.org/wiki/Special:CentralAutoLogin/start?type=1x1" alt="" title="" width="1" height="1" style="border: none; position: absolute;" />Retrieved from "https://en.wikipedia.org/w/index.php?title=Beta_blocker&oldid=672097058" Categories:

Beta blockers Scottish inventions

Connection between Alpha Synuclein, essential tremor, and beta blocker interaction

Tremor Leonid L. Rubchinsky et al. (2007), Scholarpedia, 2(10):1379.

doi:10.4249/scholarpedia.1379

revision #135551 [link to/cite this

article]

Post-publication activity

Curator: Karen A. Sigvardt

Contributors:

 

0.50 -

Leonid L. Rubchinsky

0.38 -

Eugene M. Izhikevich

0.38 -

Alexey S. Kuznetsov

0.12 -

Andrey Dovzhenok

0.12 -

Leo Trottier

0.12 -

Benjamin Bronner

0.12 -

Vicki L. Wheelock MD

Tobias Denninger

Nick Orbeck

Marc-Oliver Gewaltig

Prof. Leonid L. Rubchinsky, Indiana University

Purdue University, Indianapolis, IN, and Indiana

University School of Medicine, Indianapolis, IN,

USA

Dr. Alexey S. Kuznetsov, Indiana University

Purdue University, Indianapolis, IN

Dr. Vicki L. Wheelock MD, University of

California Davis , Sacramento, California

Dr. Karen A. Sigvardt, Department of Neurology

and Center for Neuroscience, University of

California Davis & VA Northern California HCS

Tremor is an involuntary, rhythmic oscillatory movement of at least one functional

body region.

Contents

 [hide] 

1 Introduction

2 Classifications of tremors

3 Physiology of some tremors

3.1 Parkinsonian tremor

3.1.1 Description

3.1.2 Pathophysiology

3.1.3 Origin

3.1.4 Animal models

3.1.5 Dynamics of tremor-supporting networks

3.1.6 Treatment

3.1.6.1 Pharmacological treatment

3.1.6.2 Surgical treatment

3.2 Essential tremor

3.2.1 Description

3.2.2 Pathophysiology

3.2.3 Origin

3.2.4 Dynamics of tremor-supporting networks

3.2.5 Treatment

3.2.5.1 Pharmacological treatment

3.2.5.2 Surgical treatment

3.3 Physiological tremor and enhanced physiological

tremor

3.3.1 Description

3.3.2 Properties

3.3.3 Dynamics of tremor-supporting networks

3.4 Orthostatic tremor

3.5 Other tremors

4 Summary

5 References

6 External Links

Introduction

Tremor is found in every person, typically a barely visible tremor that occurs when

the arms are extended and that is also observed during activities that require great

precision. Pathological tremor occurs in a number of conditions, where it can

appear as an isolated phenomenon, or together with other signs and symptoms.

There are several practical methods of tremor diagnosis (for clinically oriented

references, see Elble and Koller, 1990; Findley and Koller, 1995). While tremor

amplitude and frequency are important features, they are insufficient for tremor

classification. Even though time-series analysis methods have been suggested to

detect, classify and diagnose tremors, none of the available methods is simple and

efficient; therefore, observation by a neurologist dominates clinical practice.

For patient-oriented information about treatment of tremor and related conditions,

one may look at the NIH web site

http://www.ninds.nih.gov/disorders/disorder_index.htm and WE MOVE web site

http://www.wemove.org

Classifications of tremors

Clinical neurological features are traditionally used to differentiate between

tremors.

Resting tremor occurs when the affected body

part is not active and is supported against gravity.

Action tremor occurs during voluntary muscle

activation, and includes numerous tremor types.

Postural tremor occurs while the affected limbs

are voluntarily maintained against gravity, such as

when the patient extends the arms forward in front

of the body.

Kinetic tremor occurs in both goal-directed and

non goal-directed movements, as typically seen

during the finger-to-nose-to-finger test in a

neurological exam.

Intention tremor is characterized by an increase

in tremor amplitude as the target is approached.

Task-specific tremors occur during isolated tasks

such as writing.

Clinical assessment of tremor should include description of the location of tremor,

activation condition (i.e. resting or action tremor), and tremor frequency. The

presence of additional abnormal neurological signs can be an important indicator

of diagnoses such as Parkinson’s disease or other neurological disorders

associated with tremor.

Tremor may be classified in several other ways. Examples of tremor types in each

category are given in parentheses:

Normal or pathological condition:

physiological tremor

pathological tremors (with essential tremor and

parkinsonian tremor being most common).

Conditions under which tremor is most often

activated:

rest tremor (parkinsonian tremor, Holmes’

tremor, palatal tremor)

postural tremor (physiological tremor, enhanced

physiological tremor, essential tremor,

orthostatic tremor, dystonic tremor, neuropathic

tremor, psychogenic tremor)

kinetic/intention tremor (cerebellar tremor, task-

specific tremor, dystonic tremor, Holmes’

tremor)

Tremor frequency:

low frequency, less than 4 Hz (cerebellar tremor,

Holmes’ tremor, palatal tremor, drug-induced

tremor)

medium frequency, 4-7 Hz (parkinsonian tremor,

physiological tremor, essential tremor, task-

specific tremor, dystonic tremor, neuropathic

tremor, palatal tremor, drug-induced tremor,

psychogenic tremor)

high frequency, above 7 Hz (orthostatic tremor,

essential tremor, physiological tremor)

Several basic tremor types and their properties are summarized in the table below.

Properties of several basic tremor types

Tremor type Frequenc

y Activation condition

    Restin

g Postura

l Kineti

c Parkinsonian 3-7 Hz X x x Essential 4-12 Hz   X x Orthostatic 13-18 Hz   X   Physiological 3-30 Hz   X   Enhanced physiological  

8-12 Hz   X  

Cerebellar 3-5 Hz   x X Dystonic 4-7 Hz   X X Holmes' <4.5 Hz X   X Neuropathic 4-7 Hz   X   Palatal <7 Hz X     Psychogenic 4-7 Hz   X   Task-specific 5-7 Hz     X

X - characteristic condition; x - occurs in some

The differentiation between tremor categories above is somewhat blurred;

however there have been attempts to streamline tremor nomenclature for clinical

and research purposes (Deuschl et al., 1998). The amplitude of tremor does not

help to distinguish tremor types, as the same tremor type (and the same pathology)

may have markedly different amplitude. Clinical tremor rating scales include the

Fahn-Tolosa-Marin scale (Fahn et al., 1988), which assigns 0 to 4 points for tremor

amplitude under a variety of conditions and 0 – 4 points for severity in daily

activities, while the Unified Parkinson’s Disease Rating Scale (Langston et al.,

1992) assigns 0 – 4 points for amplitude and severity of resting and postural or

kinetic tremor. Rating scale scores are on average proportional to logarithm of the

displacement amplitude (Elble et al., 2006).

Physiology of some tremors

Even though each type of tremor exhibits some type of involuntary oscillatory

motion, the features of the movement and of the neuronal activity in different

tremor types can be quite different. These differences represent the differences in

the underlying physiological mechanism and/or pathological condition. Several

different mechanisms for the origin of tremor have been suggested, though for

many types of tremor, the relationship between the type of tremor and these

suggested mechanisms is not yet clearly established. Several types of tremor

mechanisms are possible (reviewed in Deuschl et al., 2001): mechanical

mechanism (every limb or limb segment has a certain resonance frequency, which

depends on the load), sensory reflex mechanisms, or central oscillator

mechanisms, i.e. pool of oscillatory neurons localized in a specific brain structure,

or manifested as a network or loop of several different structures. Here we will

consider several types of tremor, some of which are common and studied in a

detail; others are less studied, but have some interesting features.

Parkinsonian tremor

Description

Tremor associated with Parkinson disease (PD) is one of the most widely studied

and the second most common pathological tremor, with prevalence of 102-190

cases per 100,000 population in Western countries. Age at disease onset is usually

after 60 and incidence increases with advancing age (Van Den Eden et al., 2003).

Resting tremor is present in 80% of patients with autopsy-proven PD (Gelb et al.,

1999). Asymmetrical onset of tremor is commonly observed, and tremor onset may

be coincident with other parkinsonian symptoms of rigidity and slowness of

movement (bradykinesia). As PD progresses the severity of tremor may diminish.

Parkinsonian tremor is episodic tremor with the frequency typically in the range of

3-7 Hz. Tremor is accentuated by performing mental tasks or contralateral

voluntary movements ("reinforcement maneuvers") and during ambulation. In a

subset of PD patients, resting tremor may be inhibited by voluntary movement. Up

to 20% of PD patients also exhibit postural or kinetic tremor (Hughes et al., 1992).

PD is characterized by the severe degeneration of dopaminergic neurons in

substantia nigra pars compacta (SNc; Bernheimer et al., 1971; Pifl et al., 1991) and

is associated with widespread alpha-synuclein pathology (reviewed in Golbe,

2003), with the Lewy body as the pathological hallmark (Bethlem et al., 1960). The

severity of tremor is poorly correlated with the degree of dopaminergic

degeneration, but even in cases where parkinsonian-like tremor is not

accompanied by other PD symptoms (monosymptomatic rest tremor) dopaminergic

deficit is usually present (Antonini et al., 1998). PD tremor is probably linked to the

specific spatial pattern of degeneration of SNc (Paulus & Jellinger, 1991; Jellinger,

1999; reviewed in Carr, 2002).

Figure 1: Simultaneous recordings of tremor-related activity in a muscle of a tremulous

limb and basal ganglia (GPi) of a parkinsonian patient undergoing pallidotomy. GPi spikes

and EMG are weakly correlated.

Pathophysiology

Significant insights into tremor pathophysiology have been provided by analysis of

the oscillatory activity, recorded in different parts of the nervous system. Tremor-

related activity in the CNS is defined as activity in the same frequency range as

and coherent with either electromyograms from tremulous muscles or tremor

movements [Note: the term “tremor-related activity” is often used when two

signals have oscillations within the range of tremor frequencies, without an

appropriate statistical analysis of correlation.] Electrophysiological recordings in

parkinsonian patients and primate models of parkinsonism have revealed tremor-

related activity in different parts of the basal ganglia, such as globus pallidus

(primarily in the internal segment, GPi, Hutchison et al., 1997) and subthalamic

nucleus (STN, Levy et al., 2000), motor thalamus (Lenz et al., 1994) and motor

cortex (Timmermann et al., 2003). Tremor-related activity has also been observed

in the ipsilateral cerebellar cortex and contralateral premotor and somatosensory

cortical regions (Volkmann et al., 1996).

Synchronized oscillatory activity, as revealed by LFP recordings, may be important

for the function of basal ganglia and may be very widespread in PD (Hutchison et

al., 2004; Boraud et al., 2005). However it is not necessarily relevant to

parkinsonian tremor (e.g. reviewed in Rivlin-Etzion et al., 2006). Activity near or

within the parkinsonian tremor-frequency range in LFP may correspond to the

presence of involuntary movements induced by dopamine-replacement therapy –

levodopa-induced dyskinesia (Silberstein et al., 2003; Alonso-Frech et al., 2006).

Tremor-related activity may not be reflected in LFP recordings in tremulous

patients, as the LFP is an averaged signal and, thus, depends upon the phase

relationship between oscillatory units; if phase relationships are highly variable,

the oscillatory signals will be averaged out (Brown and Williams, 2005).

Origin

Multiple lines of evidence support the central generation of parkinsonian tremor.

Earlier studies showed that the proprioceptive feedback slightly modifies the

frequency of the tremor, but does not affect its existence (Pollock & Davis, 1930;

Hassler, 1970; Rack and Ross, 1986; Burne et al., 1987). The origin of the central

tremor oscillator(s) remains unknown, but several hypotheses have been put

forward (reviewed in Deuschl et al., 2000), including the rebound excitation

thalamic oscillator hypothesis (Llinas, 1984), thalamic filter hypothesis (Pare et al.,

1990), the basal ganglia pacemaker hypothesis (Plenz and Kitai, 1999; Wichmann

and DeLong, 1999), and the basal ganglia – thalamo – cortical loop hypothesis

(Lenz et al., 1993). Thalamic hypotheses are at odds with analysis of spike

correlations in thalamic activity during parkinsonian tremor (Zirh et al., 1998). The

loop hypothesis appears to be attractive, not only because anatomical and

electrophysiological data point to the existence of the loop, but also because

surgical lesions in different locations in the loop suppress tremor partially or

completely. Cellular properties of basal ganglia and thalamic cells can support

pacemaking (Surmeier et al., 2005; Llinas, 1998) and thus can contribute to the

genesis of PD tremor. Recently, computational evidence has been obtained that

further supports the basal ganglia – thalamo - cortical loop hypothesis and provides

a possible explanation for the loop mechanism of tremor oscillations (Dovzhenok

and Rubchinsky, 2012). A cerebellar origin of parkinsonian tremor has largely been

ruled out based by several lines of evidence (reviewed in Deuschl et al., 2000).

Animal models

Animal models of parkinsonian tremor are available (Burnes et al., 1983; DeLong,

1990; Bergman et al., 1998). In vervet monkeys, 1-methyl-4-phenyl-1,2,3,6-

tetrahydropyridine (MPTP) induces medium-frequency rest tremor, which

resembles human parkinsonian tremor. In the other monkey species studied, MPTP

treatment leads to either no tremor or high-frequency tremor different from PD

tremor (Wilms et al., 1999). This is probably due to the differences in the area of

the representation of the distal musculature (where tremor is most prominent) in

the basal ganglia thalamocortical neuronal networks. Nevertheless, the MPTP

primate model of PD is a source of valuable data on parkinsonian tremor.

Dynamics of tremor-supporting networks

Dual recordings in GPi tremor-related cells during stereotactic surgery have shown

that although cells may be correlated to restricted portions of the musculature or

to each other, uncorrelated oscillations within GPi are commonplace as well, even

those in the close proximity to each other (Hurtado et al., 1999). During tremor

episodes, limb specific regions of GPi are oscillatory overall, but the oscillation in

the individual tremor-related units within that region is more sporadic. The same is

true for muscular tremor. Furthermore, the synchrony between an oscillatory unit

in a particular field and a particular trembling muscle within that field is

intermittent (Hurtado et al., 2004, 2005). Coherence of tremor between muscles

differs for different muscle pairs, with muscles from the same limb having larger

coherence and muscles from different limbs (especially different sides of the body)

being largely uncorrelated (Hurtado et al. 2000; Raethjen et al., 2000). The tremor

in such muscles still may engage in short episodes of statistically significant

coherence, but the phase difference in each episode varies (Hurtado et al., 2005).

All of these findings are consistent with the view that there is a general, though not

precise, topographic organization of the individual structures that comprise the

tremor generating network, which exhibits spatiotemporal patterns of intermittent

synchronization (Hurtado et al., 2006).

Besides oscillations and synchronous activity in the tremor frequency range, cells

in STN are also oscillatory and coherent in the higher 15-30 Hz range with a very

small phase lag. This synchronization is observed in tremulous patients, even when

tremor is temporarily absent in limbs, but it is not observed in non-tremulous PD

patients (Levy et al., 2000, 2002). 1:2 phase synchronization in cortex has also

been observed in parkinsonian tremor (Tass et al., 1998).

Treatment

Pharmacological treatment

The recognition of the dopaminergic deficit in PD led to the development of highly

successful pharmacologic treatments, first with the dopamine precursor levodopa

(L-dihydroxyphenylalanine), and then with a wide array of dopamine agonists,

monoamine oxidase inhibitors and COMT (catechol-O-methyltransferase) inhibitors

(Goetz, 2005). Monoamine oxidase and COMT inhibitors slow the break down of

dopamine in the brain and, thus, can decrease the dose of levodopa needed as well

as stabilize fluctuations in motor symptoms. Older agents such as amantadine and

anticholinergics are considered second-line therapy. However, anticholinergic

drugs are sometimes useful for tremor that is refractory to dopaminergic therapy

(Nutt et al., 2005). Despite the possibility of significant improvement in motor

behavior with dopaminergic therapy, the patterns of oscillatory activity in the basal

ganglia are not fully reversed to the normal patterns of activity (Heimer et al.,

2006).

Over time, dopaminergic therapy of PD becomes less effective as complications of

on/off motor fluctuations and uncontrolled involuntary movements (dyskinesia)

develop (Lang and Lozano, 1998). Medication adjustment may help, but ultimately

10-20% of PD patients with moderate to advanced disease are candidates for

surgical treatment (reviewed in Tarsy et al., 2003; Walter and Vitek, 2004).

Surgical treatment

Surgical treatment involves placement of surgical lesions, deep brain stimulation

(DBS) and experimental cell transplantation. There are three major targets for

lesion placement: motor thalamus, GPi and STN. Thalamotomy is used to treat

tremor-dominant forms of PD (Hua et al., 2003). Pallidotomy (usually lesions in

posteroventral GPi) is less effective against tremor, but is effective against other

PD motor symptoms (Alkhani and Lozano, 2001; Baron et al., 2000). Finally,

subthalamotomy may ameliorate parkinsonian tremor, but is rarely used because

of potential side effects (Alvarez et al., 2005; Gill et al., 2003).

The target for anti-tremor thalamotomy (or thalamic DBS) is the nucleus ventralis

intermedius (Vim) of the thalamus, even though the nucleus ventro-oralis posterior

(Vop) receives input from the basal ganglia (e.g. see discussion in Jones, 2001). In

fact, Vim is an effective target for treatment of most other types of tremor, not only

parkinsonian (Ohye et al., 1976; Deuschl and Bergman, 2002; Gross et al., 2006).

However, there remains some debate whether the benefit of surgery arises from

direct effects on the targeted nucleus or from effects on areas adjacent to the

surgical target. For example, DBS in the zona incerta in close proximity to STN

may be more effective than STN stimulation (probably affecting pallido-

subthalamic pathways, Plaha et al., 2006).

The most common neurosurgical procedure for PD is deep brain stimulator

implantation (Benabid, 2003). The same structures are targeted during electrode

implantation as in ablative surgeries: STN (Abosch et al., 2003), pallidum

(Volkmann and Sturm, 2003) as well as Vim thalamus (Speelman et al., 2002).

After implantation, DBS electrodes deliver current pulses from a subcutaneously

implanted generator. Because the tissue surrounding the electrode remains

relatively intact and parameters of stimulation can be adjusted (and the electrode

can be removed surgically if necessary), DBS is favored over ablative procedures.

The frequency of effective anti-parkinsonian DBS usually lies within the 100-200

Hz range and the values around 100 Hz are considered to be the threshold rate for

the beneficiary effects of stimulation with the optimal frequencies being around

130 Hz (Volkmann and Sturm, 2003; Moro et al., 2002). During thalamic deep

brain stimulation the amplitude of parkinsonian tremor gradually decreases with

the increase of the stimulation voltage; longer duration stimulation pulses are also

slightly more effective, but the frequency of stimulation does not affect the

amplitude of tremor (O’Suilleabhain et al., 2003). The mechanisms of DBS are still

being debated, whether blockade of action potentials or synaptic modulation, and

the resultant changes in the balance of excitation/inhibition within the network or

regularization of a pathological pattern of firing (Lozano et al., 2002; McIntyre et

al., 2004). STN DBS reduces oscillatory activity and enforces more regular tonic

spiking, correlated with the stimulation signal (Meissner et al., 2005; Garcia et al.,

2005). Patients who have been treated long-term with DBS still require dopamine-

replacement therapy (reviewed in Perlmutter and Mink, 2006). Recently, attempts

of adaptive, “demand-controlled” DBS were introduced in theoretical studies

(Rosenblum and Pikovsky, 2004; Popovych et al., 2006). The idea is that adaptive

DBS will desynchronize the activity of stimulated neuronal population and thus will

suppress tremor and other symptoms. It remains to be shown experimentally that

desynchronization is technically achievable and can suppress tremor.

Finally, cell implantation (dopaminergic cells or stem cells form various sources) is

being explored for treatment of Parkinson’s disease, but in early trials tremor was

the least improved among motor symptoms. This line of treatment remains

controversial and requires further investigation (reviewed in Kuan and Barker,

2005).

Essential tremor

Description

Essential tremor (ET) is the most common movement disorder, with prevalence of

40-390 per 100,000 (Louis, 2005). Clinically, ET presents with action tremor

(postural and kinetic) with tremor frequency in the range of 4-12 Hz primarily

affecting arms, but potentially also affecting neck and head, trunk and legs. ET is a

slowly progressive, presumably neurodegenerative, disorder, which can sometimes

become very disabling. ET is inherited as an autosomal dominant disorder in 60%

of cases. The age of onset is primarily after 50 years, but there are also early-onset

cases. Many mild cases are undiagnosed. At early stages, essential tremor can be

similar to (enhanced) physiological tremor in clinical manifestations. Tremor is the

dominant symptom of the disorder and the exact underlying pathology of the

nervous system is unknown. A notable clinical feature is the tremor suppression

with alcohol ingestion. There is a debate as to whether or not ET is a

monosymptomatic disorder, and different variants of ET may correspond to

different medical conditions (for reviews on essential tremor see Deuschl and

Elble, 2000; Jankovic, 2000; Louis, 2005).

Pathophysiology

Harmaline-induced tremor in animals is generally considered to be a model for ET

because it shares many properties with ET (Ahmed and Taylor, 1959; Poirier et al.,

1966; reviewed in Wilms et al., 1999). Tremor-related activity in ET can be

observed throughout the cortico-thalamo-cerebellar circuits (Hua et al., 1998),

which is similar to tremor-related activity in basal ganglia-thalamo-cortical circuits

in Parkinson’s disease. However, in some studies (e.g., Haliday et al., 2000)

cortical activity synchronized with muscle electromyograms in the tremor-

frequency range was not found. The number of tremor units in thalamus in ET

appears to be smaller by several times than the number of tremor units in

Parkinson’s disease (Brodkey et al., 2004).

Origin

Little is known about the pathology of ET. Recent post-mortem examinations

revealed cerebellar Purkinje cell axonal swellings in several patients, and non-

nigral Lewy body formation in a single patient (Louis, 2005). Magnetic resonance

spectroscopy has revealed a reduction in cerebellar N-acetylaspartate in ET cases

(Louis et al., 2002). But so far, post-mortem brain examinations in ET provided no

solid evidence of apparent morphological changes. Nevertheless, essential tremor

probably results from olivocerebellar pathology. Lesions in different parts of the

cerebro-cerebellar-thalamic motor pathways (cerebellum, pons, thalamus) point to

the cerebellar origin of essential tremor. Studies of harmaline model of ET, as well

as the existence of other movement deficits in ET patients, support a cerebellar

origin of essential tremor (Deuschl and Elble, 2000; Deuschl and Bergman, 2002).

Dynamics of tremor-supporting networks

Irregularity in essential tremor oscillations (similar to parkinsonian tremor) can be

well approximated by second order stochastic differential equation rather than by

chaotic dynamical system (Timmer et al., 2000). Oscillatory activity in the tremor

frequency range in the brain is shown to be synchronized with essential tremor

(measured by accelerometer or as electromyogram), and properties of this

synchrony vary in space and time. Oscillations in different muscles are correlated

with each other to different degrees; the more distant muscles are from each

other, the smaller the correlation, and there is a poor correlation between tremor

on the two sides of the body (Raethjen et al., 2000). This organization led to the

hypothesis of “multiple tremor oscillators”. Similar topographical organization is

observed for cortico-muscular synchronization. Moreover, the nodes of the

essential tremor networks can be synchronous only for certain time-periods and be

out of synchrony for other periods of time (Hellwig et al., 2003). These features of

the dynamics of tremor-related activity in ET, to a degree, are reminiscent of the

dynamics of parkinsonian tremor-related activity, described above.

Treatment

Pharmacological treatment

Pharmacologic and surgical symptomatic treatments are available for ET. Since

the pathophysiology of ET is unclear, different treatment targets have been

explored. Beta-blockers (e.g., propranolol, atenolol, sotalol), anti-convulsant drugs

(primidone, gabapentin, topiramate), and GABA agonists (alprazolam, clonazepam)

are used in many patients, though their efficacy varies and side-effects can be

substantial. Propanolol and primidone have been shown to reduce limb tremor and

are the most commonly prescribed medication for the treatment of essential

tremor. Chemodenervation with botulinum toxin injections is also effective in some

patients. However, a substantial number of patients do not benefit from any

available pharmacological treatment of ET (Louis, 2005; Schast et al., 2005;

Zesiewicz et al., 2005).

Surgical treatment

Surgical treatment is available if essential tremor is disabling and not responsive

to pharmacological treatment. The techniques of surgical treatment for essential

tremor and hypotheses regarding mechanism (Hua et al., 2003; Tarsy et al., 2003)

are similar to those of parkinsonian tremor, described above. Two types of

surgeries are performed: ablative surgeries and implantation of deep brain

stimulator. The anatomical target for the surgery is Vim nucleus of the thalamus,

which is an effective target for several types of tremor (including parkinsonian

tremor). However, unlike parkinsonian tremor, basal ganglia structures

(subthalamic nucleus and internal pallidum) are not considered as anatomical

targets in essential tremor (Speelman et al., 2002, but see also Plaha et al., 2004).

During thalamic deep brain stimulation the amplitude of essential tremor slightly

decreases with the increase of the stimulation voltage (not as sharp as in

parkinsonian tremor). Longer duration of stimulation pulses is also slightly more

effective, but the frequency of stimulation does not affect the amplitude of tremor

(O’Suilleabhain et al., 2003).

Physiological tremor and enhanced physiological tremor

Description

Physiological tremor is present in all normal and healthy subjects and is exhibited

in different conditions, such as various task execution (motion or isometric

contraction), posture maintenance and even at rest. Enhanced physiological

tremor is essentially the same phenomenon, but with large amplitude oscillations,

occurring in the absence of a neurological disease. Physiological tremor can be

enhanced by the intake of stimulants and other drugs, by withdrawal from other

drugs or alcohol, during certain medical conditions (elevated thyroid hormones

levels or low glucose level), and by stress and fatigue. Physiological tremor also

becomes more enhanced with age. The frequency range for physiological tremor

can be rather wide, from 3 to 30 Hz; enhanced physiological tremor is usually

confined to 8-12 Hz range. The frequency depends on where and under what

conditions tremor is observed.

Properties

There are several factors which are believed to contribute to the genesis of

physiological tremor (reviewed in Elble and Koller, 1990; McAuley and Marsden,

2000; Deuschl et al., 2001). There is a mechanical component of the physiological

tremor – each extremity or part of it constitutes a pendulum with a particular

natural frequency, which exhibits damped oscillations for various reasons,

including cardioballistic effect. This component can have a wide range of

frequencies from about 4 Hz for elbow tremor up to 30 Hz for tremor in finger

joints). The load on the extremity results in a decrease in the frequency.

Electromyograms in physiological tremor have no clear spectral peak, primarily

because there is no muscle activity at rest and this component is, strictly speaking,

not neurogenic. Another component of physiological tremor results from the reflex

loops in the nervous system. For this component, the load on the extremity will

decrease the frequency of tremor as well as of electromyogram. Finally, there is a

central component, with the frequency in 8-12 Hz range. There were several

hypotheses of the origin of this component, including the involvement of inferior

olive and Renshaw inhibition in the spinal cord. The relative contribution of each of

these components depends on what part of the body is being considered and in

what action it is involved – rest, isometric contraction, maintenance of a specific

posture etc.

Dynamics of tremor-supporting networks

We are not aware of any comprehensive studies of spatiotemporal patterns of

synchrony in physiological tremor, but the analysis of physiological tremor in

different sides of the body showed that the coherence of physiological tremor in

two body sides is low (Lauk et al., 1999).

Orthostatic tremor

Orthostatic tremor is a rare, unique tremor characterized by subjective sensation

of loss of balance while standing, with the symptoms relieved by walking, sitting or

lying down. Clinical findings are minimal, with the observation of a visible or

palpable tremor in the trunk and lower extremities. Diagnosis is confirmed by

electromyographic recordings from the quadriceps femoris muscle revealing a

small amplitude, very high frequency (13-18 Hz) tremor while standing (Sander et

al., 1988; Britton et al., 1995). Orthostatic tremor is presumed to have a central

origin, even though the neural circuits responsible for its genesis are unknown. It

has been proposed that the brainstem is a crucial part of these circuits (reviewed

in Deuschl et al., 2001).

The distinctive feature of orthostatic tremor is its highly synchronized dynamics.

Unlike many other tremors, orthostatic tremor is characterized by high values of

coherence between tremor oscillations in different muscles, different limbs and

even different sides of the body (Deuschl et al., 1987; Lauk et al., 1999).

Treatment of orthostatic tremor is difficult as, over-all, no pharmacological therapy

produces a consistent or long-lasting effect across this patient group. The lack of

response to a particular drug may be because orthostatic tremor is not a discrete

disorder (reviewed in Gerschlager et al., 2004). Nonetheless, the treatment of

choice has been clonazepam, as well as standard therapies for essential tremor,

particularly primadone, propranolol and gabapentin. Levodopa has been reported

to be effective in some patients with orthostatic tremor (Wills et al., 1999).

Other tremors

Cerebellar tremor is a low-frequency (3-5 Hz) intention tremor (postural tremor is

also possible) due to lesions in cerebellar circuits (reviewed in Elble and Koller,

1990). Etiologies include multiple sclerosis, trauma, and hereditary cerebellar

degenerations.

Dystonic tremor is a postural or kinetic tremor usually not seen at complete rest in

a part of a body affected by dystonia. As basal ganglia circuits are frequently

implied in pathophysiology of dystonia, dystonic tremor may have basal ganglia

origins (reviewed in Deuschl et al., 2001).

Holmes’ tremor (Holmes, 1904; also known as rubral tremor, midbrain tremor,

myorhythmia or Benedikt’s syndrome) is defined as a slow frequency tremor,

usually below 4.5 Hz, both at rest and with intentional movements, occurring 2

weeks to 2 years following a cerebral injury such as stroke (the injury is presumed

to damage basal ganglia and thalamocerebellar circuits). It is typically unilateral

and affects the proximal and distal upper extremity (reviewed in Deuschl et al.,

2001).

Neuropathic tremor is most commonly seen with demyelinating neuropathies of

the peripheral nervous system such as Guillain-Barre syndrome, or chronic

inflammatory demyelinating neuropathy. There is usually a postural or action

tremor, and it can affect both upper and lower extremities. Neuropathic tremor

probably occurs due to the compensatory actions of central nervous system

(reviewed in Deuschl and Bergman, 2002).

Palatal tremor (previously known as palatal myoclonus) is a rhythmic vertical

oscillation of soft palate which can be asymptomatic, or can cause the patient to

note a clicking sound due to movement of the adjacent Eustachian tube.

Symptomatic palatal tremor follows damage to the dentate-olivary pathway, with

olivary hypertrophy visible on MRI imaging. Essential palatal tremor is an isolated

syndrome of unknown cause, and without neuroimaging correlate (reviewed in

Deuschl and Wilms, 2002).

Posttraumatic tremor is observed after certain head injuries, but the specific lesion

in the brain may not be identifiable. Posttraumatic tremor may have very different

features, depending on type of the trauma, and may have late onset or, on the

contrary, disappear following recovery (Krauss and Jankovic, 2002).

Psychogenic tremor is another tremor for which origin is not clearly understood. In

some patients it is essentially voluntary movement; in other patients it may be a

different phenomenon, where exacerbation of reflexes is involved (strong muscle

co-contraction is often observed in psychogenic tremor). Frequency is much less

stable than that of parkinsonian or essential tremor (O'Suilleabhain and

Matsumoto, 1998). The dynamics of activity of organic tremors is hard to

reproduce in voluntary movement, which suggests the use of coherence measures

to detect psychogenic tremor. Unlike most organic tremors, psychogenic tremor is

more synchronized between different limbs and can be easily entrained by external

signals (McAuley et al., 2004); however, there are patients where spatial structure

of the synchrony is similar to that in organic tremors (Raethjen et al., 2004).

Task-specific tremor is observed only during execution of a very specific motor

activity. Primary writing tremor is one example of task-specific tremor; it has a

frequency of 5-7 Hz and is induced by writing or similar motor activity (Bain et al.,

1995).

Surgical treatment (lesion or deep brain stimulation) may be effective not only

against parkinsonian or essential tremor, but also against other tremors, such as

dystonic tremor, posttraumatic tremor, tremor in multiple sclerosis, Holmes

tremor and task-specific writing tremor. Vim thalamus is usually the anatomical

target for a surgery (Speelman et al., 2002).

Summary

Tremor can be physiological or result from a known or unknown pathology, but the

physiological mechanism giving rise to tremor in any condition remains unknown.

The dynamics features of tremor within muscles of the limb segments and within

the central nervous system (frequency of tremor and correlation within and across

brain structures and muscle segments) provide clues to the nature of the

pathophysiology. Most pathological tremors, except parkinsonian tremor, are

poorly controlled by pharmacological treatment but several types of tremor are

well-controlled by deep brain stimulation in either the thalamus, internal segment

of the pallidum or subthalamic nucleus, suggesting that there is some common

mechanism that involves circuit dynamics. This hypothesis, in concert with

knowledge gained from physiological mapping of the brain during stereotactic

neurosurgery for implantation of a deep brain stimulator and from studies of

cellular and synaptic physiology of the relevant brain regions, sets the stage for

modeling studies which may provide insights into the pathophysiology of tremor.

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External Links Citation: Experimental & Molecular Medicine (2015) 47, e147; doi:10.1038/emm.2014.117Published online 13 March 2015

Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategiesOpen

Aaron Ciechanover1,2 and Yong Tae Kwon1

1Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea

2Tumor and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel

Correspondence: Dr YT Kwon, Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea. E-mail: yok5@snu.ac.kr

Received 4 November 2014; Accepted 19 November 2014

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Abstract

Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.

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Introduction

Misfolded proteins generated in various cellular compartments, including the cytoplasm, nucleus and endoplasmic reticulum (ER), are efficiently removed by quality control systems composed of the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy (Figure 1).1 The first line of defense in degrading soluble misfolded proteins is the UPS (Figure 2), a selective proteolytic system in which substrates are tagged with Ub, unfolded into nascent polypeptide chains, and cleaved into short peptides while passing through the narrow chamber of the proteasome.1, 2, 3, 4 Specific misfolded proteins that expose the KFERQ degradation signal can be degraded by the CMA, a branch of the autophagy-lysosome system (hereafter autophagy), in which substrates are selectively recognized by the chaperone heat-shock cognate 70 (Hsc70) and directly delivered into

lysosomes, leading to degradation by lysosomal hydrolases into amino acids (Figure 1).5, 6 Some misfolded proteins that escape the surveillance of the UPS and CMA or tend to form aggregates are directed to macroautophagy (Figure 1), a bulk degradation system in which substrates are segregated into autophagosomes which, in turn, are fused with lysosomes for degradation into amino acids (Figure 3).7, 8 Although almost all of the proteins encoded by the human genome can be efficiently removed from the cell when misfolded, a number of polypeptides generated from post-translational conjugation (for example, hyperphosphorylated tau in Alzheimer’s disease (AD)) or endoproteolytic cleavage (for example, amyloid β peptides) tend to be spontaneously misfolded and rapidly aggregated into oligomers enriched in β-sheet content.9, 10, 11, 12 Genetic mutations in specific proteins, such as huntingtin in Huntington’s disease (HD),13, 14 α-synuclein in Parkinson’s disease (PD),15, 16 prion protein (PrP) in prion diseases,17, 18, 19 and superoxide dismutase 1 (SOD1) and TAR DNA-binding protein 43 kDa (TDP-43) in Amyotrophic Lateral Sclerosis (ALS),20 may also perturb their folding, leading to the formation of similar β-sheet-enriched aggregates. The resulting oligomers are at least partially resistant to all known proteolytic pathways and can further grow into inclusion bodies or extracellular plaques that have highly ordered fibrillar structures with elevated β-sheet content.9 Cytotoxicity and neuronal death caused by misfolded oligomers and aggregates provide a molecular mechanism underlying the pathogenesis of many neurodegenerative diseases.21

Figure 1.

The degradation of short-lived proteins by the UPS. In this selective proteolytic system, Ub is first activated by E1 and subsequently transferred to E2. In parallel, misfolded substrates of the UPS are recognized by molecular chaperones, such as CHIP, and associated with Ub ligases that promote the transfer of E2-conjugated Ub to specific Lys residues of substrates. Ubiquitinated substrates are deubiquitinated, unfolded, fed into the narrow chamber of the proteasome, and progressively cleaved into small peptides. Depending on the types of E3 ligases, Ub can be directly transferred from E2 to the substrate or via a two-step process that involves a transient binding of E3 to Ub. The repetition of this reaction results in the growth of a singly conjugated Ub to a chain of Ub with different topologies, depending on how Ub is conjugated to another Ub. Modified from Wang and Robbins.226

Full figure and legend (80K)

Figure 2.

Autophagosome formation and lysosomal degradation. Autophagosome formation can be triggered when the mTOR complex is inhibited by various stressors, such as starvation. This induces the assembly

of the ULK protein complex composed of ULK1, Atg13 and FIP200 at the isolation membrane, which, in turn, activates the formation of the Beclin-1/PI3KC3 complex composed of Beclin-1, UVRAG, Bif-1, Ambra1, Vps15 and Vps34. During the elongation of the isolation membrane, the Atg5-Atg12-Atg16L1 complex mediates the conjugation of PE to LC3-I, generating LC3-II that relocates from the cytosol to the autophagic membrane and is anchored on its surface. The resulting autophagic membrane structures—autophagosomes—are fused with lysosomes to form autolysosomes, wherein cargoes, including misfolded proteins, are degraded by lysosomal hydrolases.

Full figure and legend (115K)

Figure 3.

The degradation of misfolded proteins by various cellular proteolytic pathways. Misfolded proteins are initially recognized by molecular chaperones that deliver the substrates to the UPS, CMA or macroautophagy depending on the nature of misfolding, size and solubility. In general, soluble and monomeric misfolded proteins are primarily degraded by the UPS and CMA. In CMA, substrates carrying the KFERQ motif are recognized and bound by Hsc70 in association with chaperones. The substrates are subsequently delivered to the LAMP2 complex on the lysosomal membrane, translocated to the lumen, and degraded into amino acids by lysosomal hydrolases. Some of these misfolded proteins tend to form aggregates and are thus directed to macroautophagy. Misfolded protein substrates of macroautophagy are recognized by molecular chaperones such as Hsc70, ubiquitinated by Ub ligases, and delivered to the autophagic adaptor p62, leading to the formation of p62 protein bodies. The targeted protein aggregates associated with p62 are subsequently delivered to autophagic membranes for lysosomal degradation, when p62 interacts with LC3 on the autophagic membrane.

Full figure and legend (136K)

Compared with proliferating cells, post-mitotic neurons are more sensitive to the accumulation of cytotoxic proteins because they cannot dilute toxic substances by means of cell division.22 Moreover, protein quality control is intrinsically challenging in neurons because of their unique cellular structure, characterized by the expansion of dendrites and axons in which protein aggregates need to be packaged into autophagic vacuoles and make a retrograde journey to the cell body, rich in lysosomes, for degradation.23, 24 Although young neurons can manage to clear cytotoxic proteins, this task becomes increasingly more difficult throughout the course of aging during which the components of the UPS,

CMA and macroautophagy are downregulated in expression and activity.25, 26 In the affected neurons of many neurodegenerative diseases, such as AD, PD, HD, prion diseases and ALS, pathogenic protein aggregates can further downregulate the activities of proteolytic pathways.27, 28, 29, 30, 31, 32 One way to enhance degradation of pathogenic protein aggregates is to increase the activities of proteolytic pathways. Many small molecule compounds have been developed and successfully used to enhance the clearance of various pathogenic proteins.33, 34, 35, 36, 37, 38

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The UPS in neurodegenerative diseases

The UPS is a proteolytic system in which the conjugation of Ub to substrates induces selective degradation by the proteasome (Figure 2).39 Protein degradation in the UPS is mediated by an enzymatic cascade composed of ~500–1000 proteins. In this ATP-consuming proteolytic system, Ub is first activated by forming a thioester bond between its C-terminal Gly76 residue and an active-site cysteine (Cys) of the Ub-activating enzyme E1. The activated Ub is transferred to the Ub-conjugating enzyme E2 via a thioester bond. It is the Ub ligase E3 that selectively recognizes and mediates ubiquitination of substrates, which involves the transfer of E2-conjugated Ub to lysine (Lys) residue(s) of the target substrate. The human genome is estimated to encode >500 E3 ligases, which can be classified into three groups depending on the types of ubiquitination domains, including the really interesting new gene (RING) finger, the homologous to E6-AP (HECT) domain and the U-box domain.40 An E3 Ub ligase can be a single polypeptide or a subunit of a protein complex, such as the SCF (Skp1-Cullin1-F-box) E3 complex. As Ub conjugation may occur at any of its seven Lys residues, a Ub chain can grow into many different topologies.41 The Lys48 linkage is the most widely used topology, which signals degradation by the proteasome, whereas the Lys63 linkage mediates non-proteolytic processes, such as Ub-dependent protein–protein interactions.42 The Lys11 linkage is typically used for cell-cycle regulation and cell division.43 Ub moieties on protein substrates can be removed by the deubiquitination enzyme to edit elongating chains or remove/recycle the targeted chains altogether from substrates.44, 45

Once ubiquitination generates a chain of four or more Ub at lysine 48, it can serve as a secondary degron that delivers the substrates to the 26S proteasome. This cylindrical machinery is composed of a proteolytic 20S core particle capped at both ends by a 19S regulatory particle.46, 47, 48 The 19S particle binds and unfolds the polyubiquitinated protein substrate and feeds the unfolded polypeptide chain into the chamber of the 20S particle, which is as narrow as 13 angstroms in diameter.47, 48 When feeding the substrates into the 20S particle, the 19S particle also deubiquitinates the polyubiquitinated substrates to recycle Ub. Passing through the 20S particle, the substrates are cleaved into small peptides by the β5, β2 and β1 subunits that have chymotrypsin-like, trypsin-like and caspase-like peptidase activities, respectively.47, 48

Substrates of the UPS include misfolded proteins, as well as a large number of short-lived proteins in the cytoplasm, nucleus, ER and other cellular compartments. The UPS-dependent degradation of misfolded proteins initiates when chaperones and Ub ligases recognize abnormalities in folding, such as hydrophobic residues exposed on the surface and improper disulfide bonds.49 Several E3s are known to mediate the ubiquitination of misfolded proteins. In the yeast Saccharomyces cerevisiae, the RING finger E3 ligase Ubr1, the recognition component of the N-end rule pathway, cooperates with chaperones to mediate the ubiquitination of misfolded cytosolic proteins for degradation by the proteasome.50, 51 The yeast Ub ligase San1 mediates the ubiquitination of misfolded proteins in the nucleus.52 With the

help of heat-shock protein 70 (Hsp70), San1 also brings excessive cytosolic misfolded proteins to the nucleus for proteasomal degradation.51, 53 The yeast HECT Ub ligase Hul5 was recently found to mediate the ubiquitination of misfolded proteins generated by heat shock.54 In mammals, the U-box-containing E3 ligase CHIP is known to interact with Hsp70 and promote the delivery of misfolded cytosolic proteins to cellular degradation machinery.55 Little is known about the mammalian Ub ligases involved in quality control of misfolded proteins in neurons.

The pathogenesis of many neurodegenerative diseases, including AD, PD, ALS, HD and prion diseases, is associated with and, moreover, at least partly contributed by the downregulation of the UPS.56, 57 One major risk factor underlying reduced UPS activities in degenerating brains is aging. Extensive studies have shown that proteasomal activities can gradually decrease with aging, which results in a reduced capacity to degrade misfolded proteins, contributing to the formation of pathological protein aggregates.27, 28, 29, 31 Another risk factor is the presence of aggregated proteins that inhibit the activities of UPS components, including the proteasome. For example, aggregated β-sheet-rich PrP blocks the opening of the 20S proteasome particle, leading to reduced proteasomal activity.58 Ubiquitinated and aggregated tau in AD can block the gate of the 19S catalytic particle by binding to its recognition site, leading to a traffic jam and impaired proteasomal degradation.30, 32 In addition, recent studies have shown that aggregates of many other pathogenic proteins in neurodegenerative disorders can directly inhibit proteasome activity.59, 60, 61, 62

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The autophagy-lysosome system in neurodegenerative diseases

Autophagy is a process by which cytoplasmic constituents are degraded by the lysosome. Protein quality control via autophagy is particularly important for the timely removal of aggregated forms of pathogenic proteins in neurodegenerative diseases, including tau in AD, α-synuclein in PD and polyQ-Htt in HD.63, 64 Autophagy can be divided into microautophagy, CMA and macroautophagy, depending on the mechanism by which cellular cargoes are delivered to the lysosome (Figure 1).65 Among the three arms of autophagy, the targeted clearance of misfolded proteins is mainly mediated by CMA and macroautophagy. CMA is a selective proteolytic system in which specific misfolded proteins carrying the KFERQ motif are delivered to and degraded in lysosomes. This pentapeptide motif, found in ~30% of cytosolic proteins, is normally buried by protein folding, but it can be exposed on the surface by misfolding or partial unfolding. It is recognized by the chaperone Hsc70 associated with cochaperones.6 The substrates are subsequently delivered to the CMA adaptor (lysosomal membrane-associated protein 2A (LAMP-2A) on the lysosomal membrane, unfolded, translocated into the lysosomal lumen and degraded into amino acids. In degenerating neurons, CMA can be constitutively activated to compensate for impaired macroautophagy.66

In macroautophagy, a portion of cytoplasmic constituents, such as misfolded proteins and organelles, are segregated by double-membrane structures called autophagosomes and subsequently digested by lysosomal hydrolases (Figure 1). The delivery of misfolded proteins to autophagosomes involves specific adaptors, including the p62/SQSTM-1/sequestosome.67 The autophagic adaptor p62 has a UBA (Ub association) domain that interacts with polyubiquitin chains of misfolded proteins and a PB1 domain that mediates self-aggregation to form condensed cargo-p62 complexes.68, 69, 70 Cargo-loaded p62 and its aggregated complexes are delivered to autophagic vacuoles through the specific interaction of p62 with light chain 3 II (LC3-II), an active form of LC3, on the surface of autophagic double membrane

structures.71 By inducing aggregation and eventually delivery to autophagic vacuoles, p62 reduces the toxicity of a free form or oligomeric species of misfolded proteins destined for macroautophagy.72 Mutations in the p62 gene have been implicated in the pathogenesis of Paget disease of bone as well as familial and sporadic ALS.73 In addition to p62, other autophagic adaptors, such as NBR1, NDP52, optineurin (OPTN), histone deacetylase 6 and NIX26, mediate the delivery of various types of cellular cargoes to autophagic membranes through similar mechanisms.74, 75 Once misfolded proteins are loaded to phagophores, the autophagic membrane structures are fused with each other to grow into autophagosomes, which are fused in turn with lysosomes, generating autolysosomes in which cargoes are degraded by lysosomal hydrolases. Autophagosome formation involves a large number of proteins and their post-translational modifications, such as the ATG7-mediated conjugation of ATG5 (autophagy-related protein 5) to ATG12, leading to cleavage and lipidation of LC3-I to form LC3-II (Figure 3).7, 76, 77 Upon conversion, cytosolic LC3-II is translocated to autophagic membranes and acts as an anchor to receive cargoes through interaction with autophagic adaptors.

Although misfolded proteins can be immediately and directly delivered to autophagosomes, excess misfolded or damaged proteins and their aggregates that accumulate beyond cellular capacity are temporarily stored in the aggresome, a cytoplasmic inclusion in the microtubule organizing center near the nucleus.9 During this process, called aggrephagy, the histone deacetylase 6, in association with molecular chaperones, binds freely floating ubiquitinated aggregates and delivers them via microtubules to a location that minimizes their toxicity until they are finally degraded by the UPS or macroautophagy.78, 79, 80, 81 The major components of aggresomes include ubiquitinated proteins as well as specific regulatory proteins involved in the formation and degradation of proteins aggregates, such as p62, ALFY (autophagy-linked FYVE protein) and NBR1 (neighbor of BRCA1 gene).

The functions and survival of neurons heavily depend on the efficient removal of misfolded proteins by autophagy because they cannot dilute cytotoxic proteins by cell division. In addition, autophagy is an intrinsically challenging process in neurons because of their unique cellular structure characterized by the expansion of dendrites and axons. For example, misfolded proteins that have been generated in axons and nerve terminals are packaged on site into autophagosomes and make a long retrograde journey to the cell body, wherein lysosomes are enriched in the perinuclear microtubule-organizing center.22 Before reaching the cell body, autophagosomes in the process of retrograde transportation often fuse with late endosomes generated in neurites, resulting in the formation of amphisomes.23, 24 This is a time-consuming, difficult and complicated process whose overall efficiency can be adversely affected by many factors, such as aging and genetic mutations. Extensive studies have shown that many components of CMA and macroautophagy are downregulated at the levels of transcription, translation and post-translation as neurons age.25, 26 These age-sensitive regulators include the substrate recognizer/carrier Hsc7082, 83 and the Hsc70-acceptor LAMP-2A in CMA84 as well as Beclin-1 in macroautophagy.85, 86 Reduced autophagic activity appears to be pharmaceutically manageable, as the restoration of CMA by maintaining LAMP-2A levels in aging mouse livers has been shown to promote liver health and increase the ability of hepatocytes to degrade damaged proteins.84 In addition to reduced autophagic activity in aged neurons, the activities of autophagic components can be adversely affected by interaction with protein aggregates,87, 88, 89 which can be excessively generated by age-dependent impairment of the UPS. For example, tau in frontotemporal lobar dementia with Ub-positive inclusions and α-synuclein in PD bind LAMP-2A with an unusually high affinity, leading to a traffic jam during cargo translocation across the lysosomal membrane.89 Yet another risk factor underlying

dysregulation of autophagy in aged neurons is a genetic mutation in a regulator of autophagy, such as p62, whose mutations are implicated in the pathogenesis of familial and sporadic ALS32, characterized by p62-positive inclusions in affected neurons.90

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Protein quality control in AD: Aβ and tau

AD is the most common form of progressive dementia, characterized by cognitive impairment, memory loss and behavioral abnormalities. This protein misfolding disorder is caused by the misfolding and aggregation of amyloid β peptides and tau, which give rise to amyloid plaques and neurofibrillary tangles, respectively.91 Aβ is a 42-residue product resulting from two sequential cleavages of the amyloid precursor protein (APP), a transmembrane protein with no clearly defined function. The first cleavage produces a C-terminal fragment, and the fragment is then cleaved by the γ-secretase complex composed of presenilin-1, APH-1, PEN-2 and nicastrin92 to generate Aβ, which tends to be misfolded to form aggregates.10, 11 Mutations of various genes, including APP, can upregulate the production of Aβ, contributing to the pathogenesis of AD.10, 11 By contrast, APP and Aβ can be downregulated by the UPS at various steps of processing, from the ER lumen to the plasma membrane.93 The first UPS degradation occurs after a nascent APP polypeptide is cotranslationally translocated into the ER lumen, during which its signal peptide is cleaved off. Following translocation, a successfully folded APP mature protein enters the Golgi secretory pathway. However, terminally misfolded APP is degraded via ER-associated degradation in which substrates are unfolded, ubiquitinated, retrotranslocated across the ER membrane and degraded by the proteasome. The targeting by ER-associated degradation involves the E3 Ub ligases HRD194 and Fbxo2.95 Proteasomal degradation can also occur when APP arrives at the Golgi apparatus, where APP is ubiquitinated though a K63 linkage by unknown E3 ligases stimulated by ubiquilin-1, leading to the retention of APP without proteasomal degradation.96 Even after being presented at the plasma membrane, APP can be internalized to endosomes and enter the endosome-Golgi pathway, where APP can be cleaved to generate Aβ.97 The resulting intracellular Aβ is prone to misfolding and is targeted by UPS-dependent protein quality control, which includes the E3 ligase CHIP that mediates the ubiquitination of misfolded proteins for proteasomal degradation.93 In contrast to APPs, however, Ub-conjugated Aβ in affected neurons is not properly degraded through the proteasome.98

Recent studies have implicated autophagy in the turnover of Aβ. In an AD mouse model overexpressing Aβ, haploinsufficiency of Beclin-1 reduced autophagy and exacerbated AD pathology, as evidenced by Aβ deposition and neurodegeneration, which was rescued by lentiviral administration of Beclin-1.99 Conditional mutant mice lacking ATG7 in the central nervous system showed degeneration of pyramidal neurons in the hippocampus and Purkinje cells in the cerebellum.100 Genetic inactivation of other autophagic components in neurons, such as ATG5 or ATG17/FIP200, resulted in similar neuronal degeneration.25, 101 While the turnover of Aβ involves autophagy, autophagy itself is impaired in the brains of AD patients. For example, affected neurons in AD brains are enriched in autophagosomes and other types of autophagic vacuoles that together act as a major intracellular reservoir of cytotoxic peptides.102 The excessive accumulation of immature autophagic vacuoles in senile neurons is associated with increased synthesis of autophagic core components, retrograde transportation of autophagosomes and impaired fusion with lysosomes, contributing to the accumulation of pathogenic Aβ.103, 104

Another hallmark of AD is neurofibrillary tangles composed primarily of phosphorylated tau.105 Although neurofibrillary tangles were initially thought to be one of the major causes of AD pathogenesis,106 recent studies indicate that a monomeric form of tau with pathological modifications and its soluble oligomers may be more cytotoxic.12 The tau protein can lose its function through various proteolytic events, including cleavage by endoproteolytic enzymes such as caspases,107 calpain,108 aminopeptidases109 and thrombin.110 However, these cleavages are unlikely to contribute to the clearance of neurofibrillary tangles because the resulting cleavage products with various modifications may aid the development of AD. The first line of defense against tau accumulation is the E3 ligase CHIP, which mediates the ubiquitination of tau (primarily in its phosphorylated form), in collaboration with Hsp70 and Hsp90 (Figure 4).111 An in vitro study showed that the E2 enzyme Ube2w can also mediate E3-independent ubiquitination of tau.112 However, ubiquitinated tau is not a good substrate of the proteasome and thus accumulates as detergent-resistant aggregates, leading to the formation of neurofibrillary tangles in AD. In the process of targeting tau to the proteasome, CHIP also appears to be deposited to neurofibrillary tangles with its substrate and other ubiquitinated proteins.98, 111 It has been shown that UPS-dependent clearance of tau is facilitated by overexpressing the molecular chaperone Hsp70, which binds misfolded proteins.111 As UPS-dependent degradation of tau is not efficient, autophagy has a close relationship with AD pathogenesis with respect to the formation of amyloid plaques and tau aggregates.113 For example, autophagic inhibition by 3-methylamphetamine or cloroquine was shown to slow tau clearance, leading to tau aggregation.114 By contrast, rapamycin, an inducer of autophagy, inhibited the accumulation of tau aggregates and neurotocixity using a mouse tau model.37 Pharmaceutical inhibition of phospholipase D1, which regulates autophagosome maturation downstream of Vps34, resulted in neuronal accumulation of tau and p62 aggregates.115 A subpopulation of caspase-generated tau fragments has been shown to be delivered to autophagic vacuoles.116 Defective autophagic flux promotes the formation of tau oligomers and insoluble aggregates. A phosphorylated form of tau shows reduced binding to microtubules and bundling as well as an increased tendency to be found as motile particles.117

Figure 4.

The degradation of tau proteins. Tau can be targeted by both the UPS and macroautophagy, depending on the nature of post-translational modifications that influence folding and solubility. In general, soluble monomeric tau proteins are recognized by molecular chaperones and Ub ligases, such as CHIP, leading to the formation of ubiquitinated tau proteins. It remains unclear as to what extent ubiquitinated tau proteins are actually degraded by the proteasome. Alternatively, the same substrates can be directly delivered to the 20S proteasome without ubiquitination. Some tau proteins prone to rapid aggregation, such as hyperphosphorylated species, can be delivered to p62 and, subsequently, autophagosomes for lysosomal degradation. Modified from Chesser et al.227

Full figure and legend (152K)

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Protein quality system in PD: α-synuclein

PD is the most common neurodegenerative movement disorder. It is characterized by decreased motor ability and the loss of dopaminergic neurons in the substantia nigra pars compacta. The major pathogenic agent of PD is a mutant form of α-synuclein, a presynaptic nerve terminal protein.118 The activity of mutant α-synuclein as an autosomal dominant cause for PD is associated with point mutations (for example, A53T, A30P and E46K) that render α-synuclein prone to misfolding and aggregation.119, 120, 121 The accumulation of aggregated mutant α-synuclein leads to the formation of intracellular inclusions called Lewy bodies (LBs), which serve as the major hallmarks of both sporadic and familial PD. In addition to mutant α-synuclein, LBs contain more than 90 proteins, including PD markers (DJ-1, LRRK2 (leucine-rich repeat kinase 2), Parkin and PINK-1 (PTEN-induced putative kinase 1)) and mitochondria-related proteins, as well as components of the UPS and autophagy, particularly those involved in aggresome formation.122, 123, 124 Consistent with the finding that many of the proteins accumulated in LBs are involved in protein quality control, major causative mutations in familial PD are linked to genes in the UPS or autophagic pathways, including α-synuclein, PINK-1, the Ub ligase Parkin, UCH-L1 (Ub carboxy terminal hydrolase L1), DJ-1 (PARK7) and LRRK2/PRAK8.122 In the pathogenesis of PD, monomeric and non-fibrillar mutant α-synuclein molecules may be more cytotoxic than fibrillar aggregates, and LBs found in the brains of PD patients may be a consequence of cytoprotective responses.122, 123, 124

Wild-type α-synuclein has been shown to be ubiquitinated and degraded by the proteasome using in vitro assays89, 125, 126 and cultured neuronal cells under proteasomal inhibition.127, 128, 129 However, other studies have suggested that ubiquitination is not needed for proteasomal degradation of α-synuclein (Figure 5).130, 131 Proteasomal degradation of α-synuclein has been shown to be facilitated by its phosphorylation at Ser129.132 Several regulatory proteins of the UPS were implicated in the turnover of soluble α-synuclein in the cytosol, including Ub ligases CHIP,133 SIAH,134, 135 MDM2136 and HRD1.137 A subpopulation of α-synuclein associated with membranes in the endosome-lysosome pathway has been shown to be targeted by the Ub ligase Nedd4.138 In addition to Ub ligases, rare mutations in the deubiquitinating enzyme UCH-L1 have been associated with familial, early onset PD.139 PD-linked mutants of UCH-L1 contain only partial deubiquitinating activities, contributing to the accumulation of α-synuclein in presynaptic terminals.140 The role of UCH-L1 in PD pathogenesis is in part attributed to its activity as an E3 ligase, whereby it mediates K63-linked ubiquitination in its dimer form.141 The overall importance of the UPS in the turnover of α-synuclein is further supported by the finding that conditional knockout mice lacking Psmc1, a proteasomal subunit, in nigral or forebrain neurons resulted in the formation of intraneuronal LB-like inclusions positive for Ub and α-synuclein associated with neurodegeneration.142 While soluble α-synuclein is degraded by the proteasome, its filamentous form can interact directly with the 20S core of the proteasome and decrease its proteolytic activity.61 Consistently, proteasome misregulation has been observed in the substantia nigra of PD patients.143

Figure 5.

The degradation of α-synuclein by cellular protein quality control. Wild-type and mutant α-synuclein can be targeted by the ubiquitination-dependent UPS (A) and possibly in a manner independent from Ub (B) as well. Monomeric α-synuclein can also be targeted by the CMA (C). By contrast, macroautophagy can degrade monomeric and oligomeric α-synuclein as well as its aggregates (D). Intracellular α-synuclein can also be cleaved by endopeptidases, such as calpains (E) and neurosin (F). Extracellular α-synuclein can be cleaved by neurosin (G) and metalloproteinases (H). The resulting proteolytic cleavage products are thought to contribute to the cytotoxicity of α-synuclein. Modified from Xilouri et al.228

Full figure and legend (107K)

Recent studies have shown that α-synuclein can be degraded by CMA through a specific CMA recognition motif.89, 144 However, the A30P and A53T PD-linked mutants have unusually high affinity for the CMA adaptor LAMP-2A and are not efficiently delivered to the lysosomal lumen, resulting in a traffic jam in CMA.89, 145 This, in turn, can trigger compensating macroautophagy.146 The hydrolysis of CMA-targeted α-synuclein in the lysosomal lumen involves cathepsin D, a primary lysosomal protease.147, 148 Although α-synuclein in a monomeric or soluble oligomeric form can be targeted by both the UPS and the CMA, its aggregates are directed to the lysosome via macroautophagy. The role of macroautophagy in α-synuclein degradation was suggested by the finding that α-synuclein is accumulated in the lysosome of cultured neuronal cells under macroautophagic inhibition, whereas the lysosomal targeting of PD-linked mutant α-synuclein was attenuated under the same conditions.33, 149 Pharmacological activation of macroautophagy using rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, facilitated the degradation of both wild-type and mutant α-synuclein.138, 150 The clearance of α-synuclein by macroautophagy was further shown in transgenic mice virally overexpressing Beclin-1, an autophagic regulator.150

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Protein quality control in HD: mutant huntingtin proteins

HD is an autosomal dominant neurodegenerative disorder that affects ~5–10 individuals per 100 000.151 Affected individuals suffer from progressive motor and cognitive declines associated with loss of self and spatial awareness, depression, dementia and increased anxiety. This progressive neurodegenerative disease is caused by the aggregation of mutant huntingtin (mHTT) proteins. The wild-type huntingtin protein (HTT) contains a stretch of the glutamine residue, called polyQ tract, which is encoded by a repeat of the codon CAG within exon 1 of the HTT gene.152, 153 The length of the CAG repeat varies between individuals and generations, ranging on average between 16 and 20 repeats.154 In affected individuals, the CAG repeat expands to >35 in number, giving rise to the elongated polyQ

tract of mHTT proteins that are prone to aggregation and toxic to neurons.14, 155 PolyQ inclusions are abundant in highly ordered amyloid fibers with enriched β-sheets and low detergent solubility.156 PolyQ inclusions may be a consequence of a protective mechanism to sequester small oligomeric forms of mHTT, which are highly cytotoxic to neurons.157 Extracellular polyQ aggregates can be internalized by cells to initiate a new round of polyQ aggregation, suggesting that mHTT may act as an infectious agent through a mechanism observed in prion diseases.158

Despite the importance of mHTT in the pathogenesis of HD, surprisingly little is known about the mechanism by which cytotoxic mHTT is removed from the cell. This is perhaps because mHTT is a poor substrate for all known proteolytic pathways, including UPS, CMA, and macroautophagy. Moreover, extensive studies have shown that mHTT acts as an inhibitor of proteolytic machineries, often in the process of its turnover.159 For example, mHTT inclusions in the brains of HD patients and HD mice are enriched in the components of the UPS, such as Ub and ubiquitinated HTT, because mHTT species can be initially tagged with Ub but are poor substrates for the proteasome.160 It has been suggested that the accumulation of mHTT inclusions is not a consequence of direct proteasomal inhibition but rather result from the gross failure of protein quality control systems in association with the sequestration of molecular chaperones.161

Wild-type HTT can be degraded by CMA,162 during which Hsc70 recognizes two KFERQ-like motifs, KDRVN at residues 99–103 and NEIKV at residues 248–252.159 Like HTT, mHTT can also be recognized by Hsc70 for CMA degradation.159 However, the polyQ expansion of mHTT delays the delivery of mHTT across the lysosomal membrane because mHTT has a higher affinity for Hsc70 and LAMP-2A.159 Failure to promptly deliver the initially targeted mHTT to the lysosome results in a traffic jam in CMA-dependent autophagic degradation, leading to a secondary side effect in proteostasis. Failure to degrade mHTT results in the accumulation of perinuclear cytoplasmic aggregates and intranuclear inclusions in the neurons of patients with HD.162

Core components of macroautophagy, such as LC3, are typically upregulated in various HD mouse models and in neuronal and non-neuronal cells in patients with HD.163, 164 The apparent upregulation of macroautophagy is associated with the excessive formation of cargo-free autophagic vacuoles, possibly because the delivery of cargoes to autophagic vacuoles is impaired.163 As the autophagic flux is reduced, components of macroautophagy, such as p62, LC3-II, mTOR and Beclin-1, were found to be deposited in the striatum of HD transgenic mice.165 The sequestration of autophagic regulators in mHTT inclusions, such as mTOR, contributes to the increased synthesis of autophagic core components.85, 166 Thus, HD disease progression is exacerbated by reduced activities of macroautophagy associated with HTT inhibition of macroautophagy in an age-dependent manner.

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Protein quality control in prion diseases: scrapie prion protein

Prion diseases, also known as transmissible spongiform encephalopathies, are infectious neurodegenerative disorders in humans and animals that affect the brain and nervous system, leading to spongiform vacuolation and severe neuronal loss.167 Prion diseases in animals include nature scrapie in sheep and goat,168 bovine spongiform encephalopathy (also known as mad cow disease) in cattle,169 chronic wasting disease in elk and deer,170 and feline spongiform encephalopathy in domestic cats.171 In humans, these fatal protein misfolding disorders include kuru172, Creutzfeldt–Jakob disease173,

Gerstmann–Sträussler–Scheinker syndrome174, fatal familial insomnia175 and new variant CJD (a human equivalent to bovine spongiform encephalopathy/mad cow disease).167

The transmissible agent common to these transmissible diseases is scrapie prion protein (PrPSc), an abnormally misfolded isoform of the host-encoded cellular prion protein (PrPC).18 PrPC is a glycosylphosphatidyl inositol-linked glycoprotein enriched in α-helical structure. This cell surface protein with no clearly defined function is initially translated as a 253-residue polypeptide and enters the ER wherein its signal peptide is cleaved off, generating a 208-residue mature protein. The mature PrPC polypeptide undergoes folding and is conjugated with sugar moieties during transportation via the Golgi-secretory pathway. In this process, a soluble form of misfolded PrPC is normally degraded by various protein quality control systems, including Ub-dependent ER-associated degradation. Compared with PrPC, however, PrPSc is enriched in β-sheets and tends to form aggregates that are at least partially resistant to all known cellular protein quality control systems.17, 18, 19 Moreover, PrPSc can interact with PrPC and facilitate the conversion of PrPC into PrPSc, which, in turn, can convert more PrPC into PrPSc, resulting in the accumulation of misfolded and aggregated PrPSc in the brain.176, 177, 178 Through this seeding-nucleation process, a small quantity of invading PrPSc is enough to trigger the autocatalytic conversion of host PrPC into PrPSc.179, 180 The transmissible nature of PrPSc has been demonstrated by the finding that the inoculation of small quantities of PrPSc into animals led to characteristics of prion diseases.177, 178

Compared with the clinical importance of PrPSc, surprisingly little is known of its turnover. In principle, as the conversion of PrPC into PrPSc requires significant refolding and conformational changes in folding, this process may involve chaperones and Ub ligases of UPS-dependent protein quality control. Indeed, recent studies in S. cerevisiae suggest that Hsp70, Hsp40 and Hsp26 may loosen prion fibrils, whereas Hsp104 fully disassembles the fibrils into shorter fragments.181 In mammalian cells, the chaperones GroEL and Hsp104 were shown to facilitate the conversion of PrPC into PrPSc in the presence of a small amount of PrPSc that served as a seed.182 In addition, Hsc70, a recognition component of CMA, was shown to bind to PrPC.183 Despite the implication of chaperones in the turnover of PrPC, it appears that PrPSc is not a good substrate of the UPS. Moreover, recent studies have shown that PrPSc binds to the 20S proteasome without further processing and thus blocks substrate entry into the proteolytic chamber, leading to proteasomal failure.62, 184 PrPSc may also bind to the external surface of the 20S particle and induce an allosteric stabilization of the closed state of the 20S proteasome.58, 185 Consistent with these findings, prion diseases are associated with impaired activities of the UPS.185 As a consequence of proteasomal inhibition, cellular Ub conjugates are excessively accumulated in mouse brain infected with ME7 scrapie train.185

Prion diseases are associated with misregulation of autophagy as evidenced by the formation of giant autophagic vacuoles in experimental scrapie in hamsters.186 These autophagic vacuoles often grow in size and number as neurons age, eventually occupying the entire volume of the affected neurites.187 The formation of giant autophagic vacuoles is caused by the reduced flux of autophagy in combination with endosomal/lysosomal dysfunction, which may contribute to the pathogenesis of prion diseases.187 Although a study showed that recombinant PrPC mutants (V203I, E211Q and Q212P) overexpressed in neuroblastoma cells were converted to PrPSc-like aggregates and delivered to aggresomes,188 there is no evidence that PrPSc is efficiently processed by autophagic pathways. Instead, recent studies indicate that prion proteins adversely affect autophagy, as exemplified by the finding that the overexpression of a PrPC-like protein, Doppel (Dpl), in neurons resulted in the progressive death of Purkinje cells in prion-

lacking Ngsk mice.189 As further described in the following sections, one way to facilitate the clearance of PrPSc is to use small molecules that stimulate autophagy.35, 190, 191

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Protein quality control in ALS: SOD and TDP-43

ALS is a progressive paralytic disease characterized by selective degeneration and death of motor neurons associated with the accumulation of misfolded proteins and insoluble inclusions.20 Although indistinguishable in clinical symptoms, this protein misfolding disorder can be divided into sporadic ALS, which accounts for ~82% of all ALS cases, and familial ALS.20 Mutations in ALS may occur in genes encoding key components of protein quality control. This group of mutant ALS proteins includes dynein and dynactin, both involved in the retrograde transport of autophagosomes from axons to the cell body,192, 193 the autophagic adaptor p62,73 and the UBA-containing proteins Ubqln2 and Optineurin.194 Another group of ALS mutations generates proteins with abnormal folding, leading to aggregation and the formation of insoluble inclusions.20 This latter group includes SOD1, TDP-43, and FUS/TLS (Fused in Sarcoma/Translocated in Sarcoma).20, 195 Approximately 20% of familial ALS cases are caused by over 140 different point mutations of SOD1, a soluble cytosolic enzyme that dismutates superoxide radicals to H2O2.196 SOD1 mutants are mostly dominant and causative to the death of affected motor neurons because they tend to be misfolded and form protease-resistant aggregates.195 Another ASL-relevant gene is TDP-43, in which mutations account for ~5% of sporadic ALS and 3% of familial ALS cases.20 This hnRNP family member can bind to RNA in a single-stranded and sequence-specific manner, which is required for many RNA processes.197 One unique aspect of TDP-43 is the property of its C-terminal tail to be prone to misfolding and aggregation.197, 198 Like other pathogenic mutant proteins in neurodegenerative diseases, misfolded SOD1 and TDP-43 mutants are initially targeted for degradation by the components of the UPS, such as chaperones and Ub ligases.20 Owing to their tendency to aggregate, however, the targeted mutants escape during the delivery process to the proteasome, some of which are redirected to autophagy. ALS mutants resistant to the UPS and autophagy are aggregated together to form intracellular inclusions containing Ub and Ub ligases found in familial ALS mutant mice199, 200 and post-mortem spinal cord of sporadic ALS patients.201, 202, 203 It was reported that the insoluble inclusions typically become visible in the brain stem and spinal cord at the onset of ALS symptoms and progressively accumulate throughout late stages.204 Although large inclusions are clinical hallmarks of ALS symptoms, they are unlikely to be toxic to neurons. They may, however, be a neuroprotective phenomenon, as it was suggested that monomeric and oligomeric misfolded ALS proteins are the actual toxic substance in motor neurons.195

Autophagy is often misregulated in the spinal cord of sporadic ALS patients, as evidenced by the excessive formation of autophagosomes.205 The autophagic misregulation can be partially explained by findings stating that inclusions observed in ALS patients can impair protein quality controls by sequestering various components ranging from proteasomal subunits and Ub ligases, such as Dorfin, to molecular chaperones HSP70 and HSP40 and the motor protein dynein involved in cargo delivery to the aggresome.5, 206, 207 Monomeric or oligomeric ALS proteins can also directly inhibit both proteasomal activity197, 198, 208, 209 and autophagic flux.210, 211, 212 Moreover, it has been shown that reduced proteasomal activity can promote the accumulation of ALS protein aggregates.213 Thus, one mechanism underlying the pathogenesis of ALS is a vicious cycle between misfolded proteins and proteolytic

pathways, which accelerates the excessive accumulation of insoluble inclusions, leading to the death of affected motor neurons.

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Targeting autophagy for therapy of neurodegenerative diseases

Substantial benefits of therapy could be achieved with agents that promote the degradation of pathogenic proteins underlying neurodegenerative diseases. Many small molecules that induce autophagy have been developed and shown to be effective in removing pathogenic proteins. The therapeutic activities of the autophagic inducer rapamycin, an inhibitor of mTOR, have been demonstrated using transgenic mouse models of neurodegenerative diseases, such as AD mice expressing mutant APP,36, 38 AD mice expressing tau,37 HD mice expressing mHTT,214 PD mice expressing mutant α-synuclein33 and prion disease mice expressing PrPSc.35 The overall results indicate that rapamycin promotes the clearance of these pathogenic protein aggregates, improves cognition and behavior and ameliorates neuropathology and neurodegeneration in the brains of these transgenic mouse models. Similar therapeutic benefits were obtained using analogs of rapamycin, such as CCI-779, which was shown to reduce mHTT aggregates, leading to improved motor behaviors in HD transgenic mice.215 In contrast, rapamycin worsened autophagic functions and neuron degeneration in a SOD1(G93A) transgenic mouse model of ALS212 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin models of PD,216 suggesting that autophagic induction may exert adverse effects on certain neurodegenerative conditions.

Various autophagic inducers were exploited to enhance the clearance of pathogenic protein aggregates in neurodegenerative diseases by targeting the ULK1 kinase AMP-activated protein kinase (AMPK) or cAMP–inositol 1,4,5-trisphosphate.13 An mTOR-independent macroautophagy inducer, Rilmenidine, was shown to improve motor ability and the clearance of mHTT fragment in transgenic HD mice.217 The mood stabilizer lithium, known to inhibit inositol monophosphatase and the phosphoinositol cycle, promoted the degradation of various protein aggregates including PrPSc of prion disease,191 mHTT of HD, α-synuclein of PD218 and SOD1 G93A of ALS.219, 220 Trehalose is a natural disaccharide product with pharmacological chaperone activity that exerts a protective role against various environmental stresses.221 This mTOR-independent autophagy activator was shown to enhance the clearance of mHTT in cultured cells, reduce the toxicity of mHTT and improve motor ability and lifespan in transgenic HD mice.221, 222 Trehalose promoted the clearance of A30P and A53T α-synuclein mutants in cultured PD model cells.221 The natural flavone finsetin and related compounds that activate autophagy through both target of rapamycin complex 1 (TORC1) and AMPK activities showed protective effects in neurodegenerative models.223 Protein phosphatase 2A agonists that inhibit tau hyperphosphorylation and activate autophagy through TORC1 and AMPK are under clinical trials for AD.224 Not surprisingly, a synergistic effect was obtained when rapamycin and Trehalose were combined to remove pathogenic protein aggregates of HD and PD.221 The combination of rapamycin and the IMPase inhibitor lithium was also shown to reduce the toxicity of mHTT.34 These results suggest that the combination therapy based on an mTOR inhibitor and an mTOR-independent activator may need to be further exploited for therapeutic application, although off-target effects are expected to increase. Collectively, these studies demonstrated that autophagic inducers have potential as therapeutic agents for selected neurodegenerative diseases. The overall effects of these reagents on a broad range of biological processes in neurons and non-neuronal cells require further investigation.

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Concluding remarks

It is estimated that there will be two billion people over the age of 60 by 2050. One common biochemical mechanism underlying most neurodegenerative disorders is the failure of protein quality control to degrade or remove misfolded proteins in the brains of aged persons. The disease-causing misfolded proteins are generated over the course of aging by post-translational modifications (for example, endoproteolytic cleaves and phosphorylation) of native proteins (for example, amyloid β and tau in AD) or genetic mutations of otherwise non-pathogenic proteins (for example, HTT in HD, α-synuclein in PD, PrPC in prion disease and SOD1 and TDP-43 in ALS). These pathogenic agents tend to aggregate into oligomers with enriched β-sheet content, which can further grow into fibrillar inclusion bodies or extracellular plaques, serving as clinical hallmarks of many neurodegenerative diseases. β-Sheet-enriched aggregates can impair—either directly or indirectly—the UPS as well as CMA and macroautophagy by interacting with various cellular molecules, including key components of proteolytic pathways. This results in the reduced ability of protein quality control, which further accelerates the accumulation of cytotoxic aggregates. This exacerbating cycle between misfolded proteins and protein quality control is particularly toxic to aged neurons as the ability of these post-mitotic cells to cope with such difficulties is naturally reduced over the course of aging. As a consequence of these unfortunate events, neurodegenerative diseases are typically associated with global failures of all proteolytic pathways.

A significant portion of cellular proteins is misfolded during translation/folding or while functioning as folded proteins, either spontaneously or under cellular stresses. Most abnormally folded cellular proteins in the human proteome can be efficiently removed through the cooperative work of the UPS, CMA and macroautophagy. In contrast, the aforementioned pathogenic proteins are commonly resistant to those proteolytic pathways, perhaps because their β-sheet-enriched folds are difficult for molecular chaperones to loosen up. These substrates, without being fully unfolded, cannot be properly fed into the proteasomal cylinder, may be stuck within the narrow cylinder of the proteasome, or may not readily dissociate from the components (for example, LAMP-2) of CMA while being delivered across the lysosomal membrane. One strategy to enhance the clearance of pathogenic proteins is to enhance the activities or levels of molecular chaperones engaged in the UPS, as demonstrated by a study in which the overexpression of the molecular chaperone Hsp70 accelerated the proteasomal degradation of tau.111 Another strategy is to activate the molecular chaperones (for example, Hsc70), carriers (for example, histone deacetylase 6) and/or adaptors (for example, LAMP-2) of CMA, as a few studies have shown that the augmentation of CMA enhanced the removal of pathogenic misfolded proteins.8, 159, 225 One common limitation of the UPS and CMA is that substrates should be at least partially or completely unfolded into nascent polypeptides before they are fed into the proteasome or lysosome. By contrast, the degradation by macroautophagy does not involve an ATP-dependent unfolding step, making this lysosomal proteolysis an ideal quality control system for aggregation-prone misfolded proteins. In addition, although autophagic flux is often reduced in affected neurons in most neurodegenerative diseases, the functions of core autophagic machinery appear to remain largely intact, as several studies have shown that the alteration of autophagic regulators such as mTOR fully restored the autophagic flux. As such, many small molecule compounds were developed to induce macroautophagy and demonstrated to enhance the clearance of cytotoxic protein aggregates. As the mTOR pathway is emerging as a promising drug target, known mTOR-dependent autophagic inducers

were successfully used to enhance the clearance of various pathogenic protein aggregates, improve cognition and behavior, and ameliorate neurodegeneration in the brains of various transgenic mouse models. Other regulators of autophagy, such as the ULK1 kinase AMPK, are also being actively exploited as potential drug targets, with synergistic effects between rapamycin and an mTOR-independent autophagic inducer. Although it is increasingly clear that autophagy inducers have therapeutic potential to remove protein aggregates, it should be noted that most of these studies use transgenic mice overexpressing pathogenic proteins that have already formed high levels of insoluble inclusions. The activities of these compounds on a broad range of biological processes, including off-target effects, should be further investigated under more physiologically relevant conditions.

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Conflict of interest

The authors declare no conflict of interest.

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Ever since PD was first described in 1817, scientists have pursued the causes and treatment of the disease. In the early 1960s, scientists identified the primary problem underlying the disease: the loss of brain cells that produce a chemical called dopamine, which helps to coordinate and control muscle activity. This discovery led to the first successful treatment for PD and suggested ways of devising new and even more effective therapies. Parkinson's research continues to be a very active field, with new and intriguing findings reported every day.

Research suggests that PD affects at least 500,000 people in the United States, and some estimates are much higher. Society pays an enormous price for PD. The total cost to the nation is estimated to exceed $6 billion annually. The financial and public health impact of this disease is expected to increase as the population ages.

In recent years, Parkinson's research has advanced to the point that halting the progression of PD, restoring lost function, and even preventing the disease are all considered realistic goals. However, we cannot yet cure any major neurodegenerative disorder, and defeating PD remains a significant challenge.

The National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH), has a long history of support for PD research. In 1997, recognizing the need to accelerate the pace of PD research, Congress signed the Morris K. Udall Parkinson's Disease Research Act into law. The Udall Act directed the NIH to expand and coordinate Parkinson's research with the purpose of finding a cure or treatment for this disease, and to award Core Center Grants — designated as Morris K. Udall Centers of Excellence for Parkinson's Disease (PD) Research — to encourage complementary research and to provide training for scientists undertaking PD research.

The Udall Centers of Excellence have embarked on diverse research avenues, but they all share a common goal:; scientific research to improve the diagnosis and treatment of patients with PD and related neurodegenerative disorders and to gain a better understanding of the fundamental

cause(s) of the disease. These centers, along with many other labs funded by the NIH, have made substantial progress in understanding PD. Some highlights of this research include the discovery and characterization of several genes linked to familial PD; the expansion of research on potential environmental factors that may underlie PD; and studies of potential new therapies, including growth factor administration, drug therapy, and deep brain stimulation.

As part of its mission to reduce the burden of neurological disease, NINDS is committed to expanding translational research – studies that translate or develop promising findings in basic research into effective treatments in the clinic. PD research is considered prime territory for translation because exciting new discoveries in basic science have accelerated our understanding of the disease over the past few years. The Institute is supporting three coordinated programs to encourage translational research projects that focus on PD and other neurological disorders. These programs provide tools and resources for therapy development, support work necessary to begin clinical testing, and offer career development and training experience for investigators interested in translational research.

The NIH conducts a vigorous and expanding program of research focused on PD. In 2000, the agency convened a workshop to create an agenda for PD research. The attendees included intramural, extramural, and industry scientists; representatives from several Parkinson's advocacy groups; and ethicists. They developed an agenda that comprises four major areas:; understanding PD, developing new treatments, creating new research capabilities, and enhancing the research process.

The PD research agenda is also relevant for other diseases. PD research can lead the way in the fight against all forms of neurodegeneration, and research on other types of neuro-degeneration also can provide vital clues about how PD may be cured.

Twelve different NIH Institutes and Centers fund research on PD, including the National Institute of Neurological Disorders and Stroke, National Institute on Aging, National Institute of Mental Health, National Institute of Environmental Health Sciences, National Human Genome Research Institute, National Institute on Deafness and Other Communication Disorders, National Institute of Nursing Research, National Institute on Drug Abuse, National Institute of Biomedical Imaging and Bioengineering, National Institute of Child Health and Human Development, National Center for Complementary and Alternative Medicine, and National Center for Research Resources. Representatives from each of these Institutes, as well as from the Department of Defense and the Department of Veterans Affairs, meet twice a year under the leadership of NINDS to discuss research and initiatives for PD, to plan meetings and workshops, and to coordinate research efforts across federal agencies. This committee is called the Parkinson's Disease Coordinating Committee (PDCC). Parkinson's is a multifaceted disease, and each of these Institutes brings a valuable perspective to confronting the biological complexities of the disorder, to pursuing the diverse therapeutic strategies showing promise, and to providing the resources necessary to carry out a research agenda of this breadth.

The NINDS also tracks PD research conducted in other countries. This worldwide tracking activity helps researchers identify potential areas for international collaboration and reduces the chance of duplicated activities.

This report serves to highlight and update the substantial progress made in PD research during the past 5 years. While the report highlights the work of the Udall Centers, many contributions have been made by other NINDS grantees and researchers around the world.

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1. Brain and Movement: The Basics

When a person initiates a movement, information from the senses, from parts of the brain that control planning, and from other brain regions travels to a region called the striatum. The

striatum then interacts with other areas of the brain — the substantia nigra, globus pallidus, and thalamus — to send out signals that control balance and coordination. These signals travel to the cerebellum, which controls muscle coordination, and then finally down the spinal cord to peripheral nerves in the limbs, head, and torso, where they control the muscles.

The molecules that carry information through the brain and spinal cord are called neurotransmitters. Neurotransmitters are special chemicals produced by neurons that accumulate in tiny sacs at the end of nerve fibers. When stimulated, these sacs release neurotransmitters into the gap between neurons, called a synapse. The neurotransmitters cross the synapse and attach to proteins called receptors on the neighboring cell. These signals change the properties of the receiving cell. If the receiving cell is also a neuron, it will carry the signal on to the next cell. If the receiving cell is a muscle fiber, it will react to the stimulation by contracting, which creates movement.

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2. What Goes Wrong In Parkinson's Disease?

The primary area of the brain that is affected by PD is the substantia nigra. It contains a specialized set of neurons that send signals in the form of a neurotransmitter called dopamine. The signals travel to the striatum via long fibers called axons. The activity of this pathway controls normal movements of the body.

When neurons in the substantia nigra degenerate, the resulting loss of dopamine causes the nerve cells of the striatum to fire excessively. This makes it impossible for people to control their movements, leading to the primary motor symptoms of PD. Many Parkinson's patients eventually lose 80 percent or more of their dopamine-producing cells.

While the neurons' underlying cause of death remains uncertain, researchers have identified several cellular characteristics that are common in this disease and which appear to play a role in the neuronal degeneration. Chief among these characteristics is the presence of Lewy bodies in neurons of the substantia nigra, the brainstem, and other parts of the brain. Lewy bodies are dense clumps, or aggregates, of proteins.

Another cellular characteristic of PD is the presence of Lewy neurites – swollen nerve fibers containing alpha-synuclein and other proteins. The accumulation of alpha-synuclein in these nerve fibers may interfere with transmission of nerve signals or other important neuronal functions.

PD is a devastating and complex disease that interferes with movement more and more as time goes on. It also produces a wide range of other problems for patients. Symptoms of the disease vary somewhat, but they may include problems with swallowing and chewing, speech impairments, urinary problems or constipation, excessive sweating and other skin problems, depression and other emotional changes, and difficulties with sleep. No one can predict which of these symptoms will affect a particular patient, and the intensity of the symptoms varies from person to person. None of these secondary symptoms is fatal, although swallowing problems can cause choking.

The progression of symptoms in PD may take 20 years or more. In some people, however, the disease progresses much more quickly. Below is one commonly used system for describing how the symptoms of PD progress.

- - - - - - - - - - - - -

Hoehn and Yahr Staging of Parkinson's Disease

Stage one

Signs and symptoms on one side only

Symptoms mild

Symptoms inconvenient but not disabling

Usually presents with tremor of one limb

Friends have noticed changes in posture, locomotion and facial expression

Stage two

Symptoms are bilateral

Minimal disability

Posture and gait affected

Stage three

Significant slowing of body movements

Early impairment of equilibrium on walking or standing

Generalized dysfunction that is moderately severe

Stage four

Severe symptoms

Can still walk to a limited extent

Rigidity and bradykinesia

No longer able to live alone

Tremor may be less than earlier stages

Stage five

Cachectic stage

Invalidism complete

Cannot stand or walk

Requires constant nursing care

Another commonly used scale is the Unified Parkinson's Disease Rating Scale (UPDRS). This much more complicated scale has multiple ratings that measure mental functioning, behavior, and mood; activities of daily living; and motor function. Both the Hoehn and Yahr scale and the UPDRS are used to measure how individuals are faring and how much treatments are helping them.

Diagnosing PD is dependent on clinical observations. There are currently no blood or laboratory tests that have been proven to help in diagnosing this disease.

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3. How Can We Treat Parkinson's Disease?

There are currently two main types of treatment for PD:; drug treatments and surgery

Drug Treatments

Medications for PD fall into three categories. The first category includes drugs that work directly or indirectly to increase the level of dopamine in the brain. People cannot simply take dopamine pills because dopamine does not easily pass through blood vessels into the brain. The most common drugs for PD are dopamine precursors – substances such as levodopa that cross the blood-brain barrier and are then changed into dopamine. Other drugs mimic dopamine, prevent or slow its breakdown, or increase the amount of it that is released.

The second category of PD drugs affects other neurotransmitters in the body in order to ease some of the symptoms of the disease. For example, anticholinergic drugs decrease the activity of the neurotransmitter acetylcholine. These drugs help to reduce tremors and muscle stiffness, which can result from having more acetylcholine than dopamine.

The third category of drugs prescribed for PD includes medications that help control the non-motor symptoms of the disease. For example, people with PD-related depression may be prescribed antidepressants.

Surgical Treatments

At present, there are two commonly used surgical treatments for PD:; pallidotomy and deep brain stimulation. Because these procedures are invasive, they are usually reserved for severely afflicted Parkinson's patients who do not get adequate relief from medications.

Brain surgery was one of the first treatments for PD. Surgeons discovered that, by removing or destroying parts of the brain that were “misfiring,” some of the symptoms of PD could be alleviated. The most common early brain operations for PD were pallidotomy, which destroyed part of the globus pallidus, and thalamotomy, which destroyed part of the thalamus. These procedures were irreversible and often led to complications. Clinicians have improved these techniques a great deal, but while they are much safer now, they are still irreversible

In recent years, scientists have found that they can mimic the effects of pallidotomy and thalamotomy by deep brain stimulation (DBS). With DBS, an electrode is implanted in the brain in a way that calms the abnormal neuronal firing. This procedure is much safer than pallidotomy or thalamotomy because the electrodes can be turned off if the patient experiences problems. The stimulation also can be adjusted to match the patient's needs. Because of this, DBS is now the primary surgical intervention for PD. In 1997, the U.S. Food and Drug Administration (FDA) approved DBS for the treatment of essential tremor using a single implanted electrode on one side of the brain. In January 2002, the FDA approved DBS for PD using two implanted electrodes — one on each side of the brain. Recently, the FDA also approved a technologically advanced electrode apparatus that can be controlled by the patient through use of a remote control device.

Complementary and Supportive Therapies

A wide variety of complementary and supportive therapies may be used for PD. Among these therapies are standard rehabilitation techniques, which can help with problems such as gait and voice disorders, tremors and rigidity, and cognitive decline. Exercise may help people improve their mobility. Physical therapy or muscle-strengthening exercises may tone muscles and put underused and rigid muscles through a full range of motion. Exercise cannot stop disease progression, but it may improve body strength so that the person can better cope with his or her disability. Researchers are studying whether exercise also may improve the response to levodopa and/or increase levels of beneficial compounds called neurotrophic factors in the brain. Targeted exercises also may improve balance, help people overcome gait problems, and strengthen certain muscles so that people can speak and swallow better. Although structured exercise programs help many patients, more general physical activity, such as walking, gardening, swimming, and using exercise machines, is also beneficial.

Some early reports suggested that dietary supplements may be protective in PD. In addition, a phase II clinical trial of a supplement called coenzyme Q10 suggested that large doses of this substance can slow disease progression in patients with early-stage PD. The NINDS and the National Center for Complementary and Alternative Medicine (NCCAM) are funding research to determine if folate, coffee, dietary antioxidants, fat, alcohol, and/or dairy products are beneficial. While there is currently no evidence that any specific dietary factor is beneficial in PD, a normal, healthy diet can promote overall well-being for PD patients just as it would for anyone else.

Other complementary therapies that are used by some individuals with PD include massage therapy, yoga, tai chi, acupuncture, ginkgo biloba (for concentration problems), and the Alexander technique, which optimizes posture and muscle activity. There have been limited studies suggesting mild benefits with many of these therapies, but they do not slow PD and there is no convincing evidence that they are beneficial.

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4. Research Findings and New Directions

During the past five years, researchers have made substantial advances in our understanding of the biological factors involved in PD. They are beginning to decipher the roles of individual genes and environmental factors in PD and to learn how the interplay of these factors can lead to the disease. Each abnormal gene or environmental factor that is identified provides another clue to help solve the mystery of PD

Genetics

Until the last decade, many researchers believed that PD was caused solely by environmental factors. However, the discovery of gene mutations in familial, or inherited, forms of PD has led to an explosion of research on PD genes and the function of the proteins that are encoded by these genes

Although most people do not inherit PD, studying the genes responsible for the inherited cases can help researchers understand both inherited and sporadic (non-hereditary) cases of the disease. The same genes and proteins that are altered or missing in inherited cases may also be altered in sporadic cases by environmental toxins or other factors.

Identifying gene defects can also help researchers understand how PD occurs, develop animal models that accurately mimic the neuronal death in human PD, identify new drug targets, and improve diagnosis. The genetic approach has been very successful, with new discoveries occurring at an unprecedented pace. The following summary highlights current knowledge about the genes known to be involved in PD, and the functions of the proteins these genes produce.

• alpha-synuclein

The first PD-related gene to be identified was alpha-synuclein. Researchers at NIH and other institutions studied the genetic profiles of a large Italian family and three Greek families with familial PD and found that their disease was related to a mutation in this gene. They found a second alpha-synuclein mutation in a German family with PD. These findings prompted studies of the role of alpha-synuclein in PD, which led to the discovery that Lewy bodies from people with the sporadic form of PD contained clumps of alpha-synuclein proteins. This discovery revealed a potential link between hereditary and sporadic forms of the disease and sparked investigations into the normal function of alpha-synuclein as well as the possible effects of alpha-synuclein mutations on normal cellular activity

One theory about how alpha-synuclein is associated with PD holds that the mutated protein interferes with cell membranes. Within the cell body, individual molecules of alpha-synuclein join together to form tiny protein threads called fibrils; this process is called fibrillization.

Investigators at the Brigham and Women's Hospital Udall Center and elsewhere have shown that mutations in the alpha-synuclein gene disrupt the fibrillization process and lead to the accumulation of protofibrils, an intermediate step in alpha-synuclein fibrillization. They found that alpha-synuclein protofibrils have protein structures which resemble bacterial and insect toxins that make membranes leaky. This could trigger cell death and may explain the toxicity of Lewy body proteins. This idea is supported by studies from the Massachusetts General Hospital and Massachusetts Institute of Technology Udall Center showing that alpha-synuclein is located near cell membranes in postmortem brain tissue from people with diffuse Lewy body disease.

Another study suggests that a buildup of normal alpha-synuclein may clog up the cell's protein disposal system and cause neurons to die. A group of researchers at NIH and other institutions investigated a rare familial form of early-onset PD and discovered that a multiplication of the normal alpha-synuclein gene, and a corresponding increase in alpha-synuclein protein, can cause the disease. The researchers analyzed blood samples from a family, the "Iowa kindred," in which many relatives developed PD or related neurological diseases. In the relatives with PD, the researchers found four copies of the alpha-synuclein gene — an abnormal triplication of three alpha-synuclein genes on one copy of chromosome 4 and one gene on the other chromosome 4 — instead of the usual two copies of the alpha-synuclein gene. This multiplication resulted in an abnormally large amount of alpha-synuclein in the cells

A third theory proposes that mutant alpha-synuclein interferes with the normal housekeeping functions of cells and lets proteins build up to toxic levels. Researchers at the Columbia University Udall Center, along with colleagues at Brigham and Women's Hospital and the Albert Einstein College of Medicine, have found that normal alpha-synuclein is broken down by lysosomes, which act as the cell's garbage disposal system. Mutant alpha-synuclein, however, blocks the pathway into the lysosomes. This inhibits the breakdown of alpha-synuclein as well as other proteins. This may trigger a toxic buildup of protein “garbage” inside the cell.

Researchers are continuing to study the alpha-synuclein gene to clarify how it affects PD.

For example, Mayo Clinic Udall Center researchers are assessing the alpha-synuclein gene in a large group of people with PD, and in a control group of healthy people who match the PD patients in age, gender, and demographics, in order to look for variations in the gene that may affect susceptibility to the disease. Investigators at the Johns Hopkins University Udall Center have developed mice with alpha-synuclein gene mutations and found that the mice accumulate alpha-synuclein in the midbrain, cerebellum, brainstem, and spinal cord and develop an adult-onset neurodegenerative disease with symptoms resembling human PD, including motor dysfunction, bradykinesia, and dystonia.

The discovery of alpha-synuclein has paved the way for other genetic linkage studies in families with PD (see the sidebar Gene Discoveries). Within the past 5 years, many regions of the genome have been linked to PD and four additional PD genes have been identified, including parkin, DJ-1, PINK1, and DRDN.

• Parkin

Genetic studies on a rare, juvenile-onset form of PD led to the discovery of the parkin gene. Originally, this form of PD was not linked to Lewy bodies. However, Mayo Clinic Udall Center scientists have found parkin mutations that are accompanied by Lewy body pathology. Further studies have shown that parkin is a part of the so-called ubiquitin-proteasome system, which breaks down proteins in the cell. This suggests that parkin mutations may lead to accumulation of toxic proteins within neurons. Researchers also have shown that parkin interacts with synphilin-1 and alpha-synuclein and mediates an important step in protein handling. When alpha-synuclein, another protein called synphilin-1, and parkin are injected together into cells in culture, they form inclusions in the cell that are similar to Lewy bodies. This suggests that parkin may be important in both inherited and sporadic forms of the disease. Several studies have suggested that normal parkin protects neurons from diverse threats, including alpha-synuclein toxicity, proteasomal dysfunction, and excitotoxicity. Other evidence indicates that parkin

degrades alpha-synuclein and that it accumulates on Lewy bodies in neurons within the substantia nigra, brainstem, and cortex of people with PD.

Findings from a different group of studies suggest that parkin may help to regulate the release of dopamine from substantia nigra neurons. In a mouse model for PD that is genetically engineered to lack the parkin gene, researchers found higher-than-normal levels of dopamine in the striatum. However, the neurons normally activated by dopamine required more stimulation to produce a response. The mice without parkin also had impairments in tests that require muscle coordination. These studies indicate that parkin may help to regulate the release of dopamine from nigral neurons.

Researchers at the Duke University Udall Center have shown that people with a parkin mutation in just one copy of the gene have a higher risk of getting PD as they get older than people without these mutations. Understanding why this happens could lead to strategies for preventing PD in people who are genetically predisposed to the disease

• DJ-1

The DJ-1 (PARK7) gene has been linked to another early-onset form of PD. This protein is involved in regulating gene activity and in protecting cells from a damaging process called oxidative stress. Mayo Clinic Udall Center researchers are screening patient samples for mutations in DJ-1, as well as other genes, to find out if these mutations are common among people with PD or restricted to just a few families. They also have evaluated DJ-1 in early-onset PD cases and identified a DJ-1 gene variation called R98Q.

Scientists at the Johns Hopkins University School of Medicine Udall Center have examined mutant DJ-1 genes in cultured human cells and found that the mutation reduces stability of the DJ-1 protein. These mutant proteins are degraded by proteasomes more quickly than usual and cannot form chains as the normal proteins do. Thus, the abnormal form of DJ-1 may not be able to perform its normal functions within the cell.

• PINK1

Mutations in a gene called PTEN-induced kinase 1 (PINK1), also known as PARK6,; have been identified in several families with PD. Kinases help to regulate protein function in both normal and disease states. The PINK1 gene codes for a protein active in mitochondria, which convert food into energy inside the cell. Cell culture studies suggest that PINK1 may help to protect the cell and that mutations in this gene may increase susceptibility to cellular stress. The discovery of this gene provides a direct molecular link between mitochondrial dysfunction and the development of PD.

• DRDN

Researchers at NIH and colleagues from several European institutions recently identified mutations in a gene called DRDN that appear to cause a late-onset form of PD. This gene, found in several English and Basque families, is located in a chromosomal region formerly called PARK8. DRDN codes for a protein called dardarin – a name derived from the Basque word for tremor. The function of this protein is still unknown.

• Other Genes That May Play a Role in Parkinson's Disease

UCH-L1 – Scientists at NIH and elsewhere have identified a mutation in the Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCH-L1) gene in a German family with PD. In addition, researchers at the Mayo Clinic Udall Center have identified a variation of the gene, also called PARK5, that is associated with an increased risk of PD in some families. UCH-L1 is an important member of the ubiquitin-proteasome system that performs “ubiquitination,” a process that tags proteins for breakdown. Ubiquitination is critical for the proper handling of misfolded proteins.

synphilin-1 – Researchers at the Johns Hopkins University School of Medicine Udall Center have found that a protein called synphilin-1 interacts with alpha-synuclein and promotes the formation of cellular inclusions resembling Lewy bodies. Studies are now underway to define the normal location and function of synphilin-1.

PACRG – This gene, called parkin co-regulated gene, was identified by researchers at the Mayo Clinic Udall Center. PACRG appears to interact with parkin and to be part of the protein degradation system.This protein also appears to be a component of Lewy bodies.

GSTO-1 and -2 – A gene called glutathione S-transferase omega-1 (GSTO-1) appears to affect the age of onset for PD and Alzheimer's disease. GSTO-1 is one of a family of genes that break down and recycle many compounds in cells, including drugs, carcinogens, and the products of oxidative stress. Studies suggest that GSTO-1 may modify an inflammatory compound called interleukin-1 beta and protect against the inflammation commonly found in brains from people with PD. Scientists also have identified a related gene, glutathione S-transferase omega-2 (GSTO-2).

tau – The tau protein is an important component of microtubules, which are part of the cell's structural support system and help to deliver substances throughout the cell. Recent studies have linked an abnormal tau protein to a parkinsonian disorder, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Additional studies have suggested that aberrations in the tau protein contribute to the pathology of sporadic PD. Mayo Clinic Udall Center researchers are sequencing the tau gene in samples from their patients with familial parkinsonism to determine if it plays a role in these forms of PD.

fibroblast growth factor 2 – This growth factor helps to maintain neurons. Studies by Duke University researchers suggest that mutations in the FGF2 gene may be a risk factor for PD.

apolipoprotein E – Duke University researchers conducting a genomic screen to identify genes influencing age of onset for PD and Alzheimer's disease have found that normal genetic variations in the apolipoprotein E protein affect the age of onset for PD, just as they do for Alzheimer's.

PARK3, PARK9, PARK10, and PARK11 – These are chromosomal regions that have been implicated in families with PD. The chromosomal regions have not been narrowed down to specific genes, but researchers are working to identify the genes and to determine their function. People with PARK3 have a relatively late age of onset, much like sporadic PD. PARK9 has been identified in one Jordanian family. PARK10 is linked to age of onset of PD in Icelandic families. PARK11 was identified in pairs of siblings and appears to affect susceptibility to the disease

The search for additional PD-related genes continues on many fronts. University of Virginia Udall Center researchers are working to define mitochondrial DNA (mtDNA) mutations that may be linked to PD. They have finished intensive sequencing of seven mitochondrial genes in frontal cortex samples from a small group of people with the disease and an equal number of controls. They found potentially important mutations in genes called ND2, ND4L, and ND5. These findings counter the hypothesis that PD is caused simply by an increase in age-related mtDNA mutations. The University of Virginia researchers also have developed methods to remove and replace the human mitochondrial genome. These technologies may lead to mitochondrial gene replacement as a method of treating PD and other sporadic neurodegenerative diseases. They could also be used to show whether these mitochondrial gene mutations cause PD and related diseases.

Duke University researchers also are investigating the role of the mitochondrial genome in PD. They have discovered that specific DNA regions and variations are associated with an increased risk of PD. This work has led to a collaborative study with the University of Virginia investigators to look more closely at how these mitochondrial DNA variations affect cellular functions.

Researchers are developing a variety of new approaches to speed research on genes and on the functions of the proteins they produce. For example, scientists at the Duke University Udall Center have developed a new approach called “genomic convergence” to study PD and other common diseases. This approach identifies and prioritizes candidate susceptibility genes for PD by taking data from gene expression studies and merging it with data from studies that detect chromosomal regions linked to PD (linkage analysis). Genes identified by the genomic convergence technique are relatively likely to play a role in PD. This combination of two powerful techniques saves investigators time and effort compared to studying the results of gene expression or linkage analysis alone. This approach has been used successfully to identify the GSTO-1 gene

Researchers at the Duke University Udall Center have performed the first large expression studies to identify genes that are abnormally active or inactive in areas of the brain affected most by PD. ; They also have compared gene activity in PD with that in similar diseases such as progressive supranuclear palsy and FTDP-17. In addition, they have helped develop new gene analysis techniques that can determine if specific genetic variants make an individual more susceptible to PD. These tests, called the Pedigree Disequilibrium Test (PDT) and Geno-PDT, have improved on previously available techniques.

Mayo Clinic Udall Center researchers have gathered information and DNA samples from more than 200 PD families. They also are collaborating with investigators from other countries. They have worked with researchers at the University of British Columbia to study affected and unaffected PD family members with positron emission tomography (PET) scans. In addition, they have screened familial PD cases for DNA expansion mutations and identified 12 families who have mutations for spinocerebellar ataxia type 2. They also have worked with the European Consortium on Parkinson's Disease to complete a preliminary genetic analysis of 350 pairs of siblings. This effort has identified five regions of the genome that appear especially significant and are being studied for potential PD genes.

Several additional large-scale efforts to identify genes that play a role in PD are underway. NINDS is helping to sponsor PROGENI (Parkinson's Research:; the Organized Genetics Initiative), which is looking at genes and other potential PD risk factors in 900 pairs of siblings in North America. Among other discoveries, this study has shown that mutations in the parkin gene may be a risk factor for late-onset PD as well as the juvenile-onset disease.

NINDS also is sponsoring a DNA and cell line repository to enhance gene discovery by supplying DNA samples, cell lines, and clinical and pedigree data to the neuroscience community.

Research on the genetics of PD also receives funding from other NIH institutes. The National Human Genome Research Institute is sponsoring a clinical study to identify people with inherited PD and to look for gene mutations in these individuals, and the National Institute of Environmental Health Sciences is sponsoring a study to look at nine candidate genes in a sample of 800 people with PD and their siblings to clarify what role these genes might play in the development of this disease.

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Environmental Factors

Although the importance of genetics in PD is increasingly recognized, many researchers still believe that environmental exposures also increase a person's risk of developing the disease. Even when genes are a factor in the disease, as with many familial cases, exposure to toxins or other environmental factors may influence when symptoms of the disease appear and/or how the disease progresses.

One of the primary pieces of evidence that environmental factors play a role in the development of PD is that the relative risk of the disease is higher in industrialized countries than in less

industrialized ones. In addition, studies have found that farmers and other agricultural workers have an increased risk of developing PD. Taken together, these studies suggest that toxic chemicals or exposure to other environmental factors present in industrial and agricultural areas might increase the risk of PD.

Another piece of evidence comes from observations of people who have been accidentally poisoned with the toxin MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine), which sometimes contaminates street drugs. MPTP is structurally similar to some pesticides. A breakdown product of MPTP, called MPP+, is toxic to substantia nigra neurons — the neurons that are affected in PD. MPTP produces a severe, permanent parkinsonian syndrome in affected people, and is now used to create animal models of PD. This discovery demonstrated that a toxic substance can damage the brain and produce parkinsonian symptoms.

A study of people in the World War II Veteran Twins Registry has suggested that genetic factors do not play a major role in causing sporadic PD that begins after age 50. However, genetic factors do appear to play a role when the disease begins at or before age 50. A number of other twin studies have found similar results. The chance that two siblings will both have PD is similar for fraternal and identical twins, suggesting that environmental exposures are more important than genetics in determining who will get the disease. Other studies have found that fraternal and identical twins of people with PD often have significant loss of dopamine neurons even when they don't experience any symptoms.

In another line of research, investigators are studying a disorder with a unique combination of parkinsonian symptoms, dementia, and motor neuron disease found in some people from the island of Guam to see if it might be due to an environmental factor or factors. A similar syndrome has been identified in people from the Kii peninsula in Japan. Researchers have long speculated that the disorder on Guam might be related to the consumption of animals that eat toxic cycad seeds found on that island. A 2002 study found neurotoxins in flour from cycad plants and showed that mice fed the cycad flour developed behavioral changes and neuron loss much like those seen in PD.

Viruses are another possible environmental trigger for PD. People who developed encephalopathy after a 1918 influenza epidemic were later stricken with severe, progressive Parkinson's-like symptoms. A group of Taiwanese women developed similar symptoms after herpesvirus infections. In the latter case, the symptoms were linked to a temporary inflammation of the substantia nigra, and later disappeared. However, these cases showed that viruses can sometimes affect the region of the brain damaged in PD. Other studies have found evidence of activated immune cells and the accumulation of inflammation-associated proteins in PD. These changes might be triggered by viruses in some cases.

Scientists are continuing to study environmental toxins such as pesticides and herbicides that can cause PD symptoms in animals. Researchers supported by the NINDS and the National Institute on Aging have shown that exposing rodents to the pesticide rotenone can cause cellular and behavioral changes that mimic those seen in PD. Work supported by the National Institute of Environmental Health Sciences has shown that other agricultural compounds also can produce abnormalities in cells that are similar to those seen in PD. This research is supported through a program called the Collaborative Centers for Parkinson's Disease Environmental Research (CCPDER) Consortium. This program sponsors a variety of projects to examine how occupational exposure to toxins and use of caffeine and other substances may affect risk, and whether inherited genetic mutations may predispose certain people to developing PD after exposure to certain chemicals.

Researchers at Rush-Presbyterian-St. Luke's Medical Center have examined whether prenatal exposure to toxins may increase the risk of PD. They found that exposure to a bacterial toxin called lipopolysaccharide during development in rats leads to the birth of animals with fewer than the normal number of dopamine neurons. This dopamine neuron loss persists into the animals' adulthood and increases with age, which mimics the course of human PD.

Along with genetic studies, these environmental studies lay the groundwork for a comprehensive understanding of how PD develops and how it might be prevented.

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Pathways to Parkinson's Disease

Many researchers are working to understand the complex cellular activities and protein interactions that may lead to PD. Cellular factors that have been implicated in PD include mitochondrial interactions, oxidative stress, programmed cell death (a biochemical chain of events by which cells self-destruct), excitotoxicity, protein aggregation, immune factors, and the ubiquitin-proteasome protein degradation system. While these factors represent many different lines of research, scientists are beginning to understand how they may fit together to form a full picture of how PD develops.

• Mitochondria, Oxidative Stress, and Programmed Cell Death

For years, mitochondria, the “energy plants” of the cell, have been implicated in the development of PD. Mitochondria are unique parts of the cell that have their own DNA (mtDNA). This DNA is separate from the genes found in the nucleus of every cell. Most research on the role of mitochondria in PD points to abnormalities in the largest component of the mitochondrial energy processing machinery — a group of proteins known as complex I.

Several lines of research suggest a mitochondrial role in protein aggregation, Lewy body formation, and neuronal death. Mitochondria are major sources of free radicals — highly unstable molecules that damage components of the cell, such as membranes, proteins, and DNA. This process is often referred to as oxidative stress. Oxidative stress-related changes, including free radical damage to DNA, proteins, and fats, have been detected in brains of PD patients

Research has shown that an array of toxins, including MPTP and a pesticide and herbicide called rotenone, can affect mitochondrial complex I and increase the number of free radicals it produces. Researchers at the Columbia University Udall Center have found that these free radicals can modify alpha-synuclein in a way that causes it to aggregate or clump together into minute fibers, called fibrils.

Investigators at Emory University have modeled the process by which mitochondrial defects produce oxidative stress by using rotenone. In rats, chronic rotenone exposure causes oxidative protein and DNA damage and increases susceptibility to free radical-induced cell death. It also leads to the same pathological, biochemical, and behavioral features seen in PD. Despite the fact that it inhibits complex I throughout the brain, rotenone causes degeneration only in dopamine neurons. Studies suggest that these neurons are selectively vulnerable to complex I impairment.

Scientists at the Duke University Udall Center have found evidence that specific genetic variations in mtDNA, known as genetic polymorphisms, can increase the risk of getting PD, while other mtDNA variations are associated with a lowered risk of the disorder. They also have found that PD patients have more mtDNA variations than patients with other movement disorders or Alzheimer's disease. Researchers still need to define how these mtDNA variations may lead to PD.

Mitochondria also are thought to initiate a process called programmed cell death. Programmed cell death, or apoptosis, is necessary for normal embryonic development. Scientists believe programmed cell death allows cells to die without disturbing their surrounding environment. However, programmed cell death also has been implicated in many neurodegenerative diseases and conditions, including PD

Several molecules are known to participate in the programmed cell death pathway; some promote cell survival while others promote cell death. An important topic in neuroscience research is the relationship between these pro-death and pro-survival molecules.

Mitochondria trigger programmed cell death by releasing a substance called cytochrome c that activates proteins called caspases and other cell death factors. Researchers believe this may occur in response to oxidative stress and mitochondrial toxins.

The idea that programmed cell death plays a role in PD has been strengthened by studies performed at the Udall Centers. For example, Columbia University scientists have discovered that, in an MPTP mouse model for PD, a pro-cell death molecule known as Bax is abundant in dopamine-producing neurons of the substantia nigra. They also showed that mice lacking the Bax gene were protected from brain damage caused by MPTP. These results suggest that programmed cell death plays a role in animal models for PD and that it also may be involved in the human disease.

Scientists at the University of Virginia Udall Center have found that treatment with MPP+, a toxic derivative of MPTP that inhibits mitochondrial complex I, influences several molecules known to play a role in programmed cell death. Interestingly, some of these changes required activation of nitric oxide, a free radical that is often expressed in injured or damaged cells. The role of nitric oxide in programmed cell death was confirmed in an experiment in which cells were treated with nitric oxide instead of MPP+. This treatment produced the same programmed cell death-related changes as MPP+. Other experiments have shown that mice lacking Bax and nitric oxide are protected against MPTP toxicity.

Investigators at the University of Virginia Udall Center also have developed hybrid cells, called cybrids, in which mitochondrial DNA from PD patients is placed in neuroblastoma (cancer) cells. These cybrids develop Lewy bodies just like those in the dopamine neurons of PD patients. The cybrid cell lines with the lowest complex I activity make the most Lewy bodies. These findings show that PD mitochondrial gene expression in a cybrid model is sufficient to spontaneously cause development of Lewy bodies, providing strong support for the idea that mitochondrial defects are key to the development of sporadic PD.

Collectively, these results demonstrate that mitochondrial-induced programmed cell death contributes to the neuronal loss in PD. This suggests that a possible treatment strategy for PD is to inhibit the cascade of events associated with programmed cell death. Accordingly, scientists have discovered that inhibiting the release of cytochrome c and caspases from mitochondria with the drugs minocycline, pramipexole, and bongkreckic acid can protect cells from degeneration. These drugs may be clinically useful as neuroprotectants to prevent PD.

• Protein Degradation (Ubiquitin-Proteasome System)

Another major area of PD research involves the cell's protein disposal system, called the ubiquitin-proteasome system. Researchers believe that if this disposal system fails to work correctly, toxins and other substances may build up to harmful levels, leading to cell death

In the ubiquitin-proteasome system, a chemical called ubiquitin acts as a “tag” that marks certain proteins in the cell for degradation by the proteasomes. The ubiquitin-proteasome system involves interactions between several proteins, including parkin and UCH-L1. This suggests that disruption of the ubiquitin-proteasome pathway is part of the mechanism by which mutations in these genes cause PD.

Studies have suggested that UCH-L1 is involved in the production of ubiquitin. Mutations in the parkin gene also interfere with normal proteasomal function. Scientists at the Johns Hopkins University Udall Center have shown that treatment with a toxin that inhibits the ubiquitin-proteasome system causes cells with mutant alpha-synuclein to be susceptible to programmed cell death. This cell death is accompanied by activation of caspases and by injury to the

mitochondria. These changes could be blocked by cyclosporin A, which prevents the release of factors that activate caspases.

Proteasome inhibition results in accumulation of molecules normally degraded by the ubiquitin-proteasome pathway, such as p53, NFKB, and Bax. These molecules help to promote programmed cell death.

• Protein Aggregation

PD is characterized by fibrillar inclusions inside the cell called Lewy bodies. Lewy bodies include clumps (aggregates) of alpha-synuclein fibrils and other proteins. There is strong evidence that this protein aggregation initiates a cascade of events that culminates in neurodegeneration. If so, then inhibiting aggregation may be a way of treating PD.

Many researchers are trying to learn the function of Lewy bodies. Some studies argue that Lewy bodies are a byproduct of degenerative processes within neurons, while others suggest that Lewy bodies are a protective mechanism by which neurons lock away abnormal molecules that might otherwise be harmful. In addition, some research suggests that protofibrils – an intermediate step in the development of alpha-synuclein fibrils – may be damaging to the cell.

Researchers at the Brigham and Women's Hospital Udall Center have found that free radicals induce formation of alpha-synuclein-dopamine compounds that stabilize protofibrils. They also showed that the alpha-synuclein in protofibrils binds to vesicles inside the cell, which could trigger cell death and may explain the toxicity of alpha-synuclein and other fibril-forming proteins. They are now studying purified proteins under carefully controlled conditions in culture to determine what factors make the proteins clump together and what structure the aggregated proteins form. They are collaborating with other researchers to develop agents that can help to image protein aggregates using single photon emission computed tomography (SPECT), and they are investigating whether PD may result from a loss of normal alpha-synuclein function, rather than from the accumulation of aggregates.

Researchers at the Massachusetts General Hospital and Massachusetts Institute of Technology Udall Center have found that alpha-synuclein aggregates lead to altered gene expression. By studying brain tumor cells, they have found that overexpression of several chaperone proteins – proteins that help other proteins fold correctly – suppresses aggregation of alpha-synuclein. However, a mutant form of one of these proteins does not decrease alpha-synuclein aggregation. Taken together, these data suggest that molecular chaperones aid the handling of misfolded or aggregated alpha-synuclein.

Aberrations in the tau protein also may contribute to the protein aggregation seen in PD. Mayo Clinic Udall Center researchers have studied a line of mice, called hTau mice, that overexpress the tau protein. These mice have neurofibrillary tangles containing both synuclein and tau, and they exhibit premature cell death early in life. Experiments show that synuclein and tau may interact to promote the fibrillization of both proteins.

• Excitotoxicity

Another common topic of PD research is excitotoxicity – overstimulation of nerve cells that leads to cell damage or death. In excitotoxicity, the brain becomes oversensitized to the neurotransmitter glutamate, which increases activity in the brain.

The dopamine deficiency in PD causes overactivity of neurons in the subthalamic nucleus, which may lead to excitotoxic damage there and in other parts of the brain. In addition, researchers have found that dysfunction of mitochondrial complex I, due to gene mutations or exposure to toxins, causes a decrease in the cell's energy supply. This can make dopamine-producing neurons vulnerable to glutamate and to an increased production of nitric oxide and other free radicals. These changes cause oxidative stress, cell death, and alpha-synuclein aggregation.

Other evidence that excitotoxicity plays a role in PD comes from a unique disease found in people from Guam. This disease features a combination of motor neuron disease, parkinsonian symptoms, and dementia, and researchers believe it results from a toxin that comes from cycad seeds and acts on glutamate receptors. This suggests that excitotoxicity is central to the development of the parkinsonian disorder in Guam.

Studies at Columbia University have shown that the normal form of parkin may play a role in preventing excitotoxicity in PD. Scientists found that parkin tags a protein called cyclin E, which accumulates in neurons that are dying from excitotoxicity, and causes its degradation. However, mutated parkin cannot trigger degradation of cyclin E. When the researchers increased the amount of parkin

in dopamine neurons that were overstimulated with a drug called kainate, they found that the parkin reduced cyclin E and prevented the cells from dying. Reducing parkin in these neurons increased the amount of cell death due to overstimulation. Interestingly, the researchers found excess cyclin E in the dopamine neurons of some patients with sporadic PD as well as in patients with the inherited form of the disease that is linked to parkin.

• Inflammation

Another interesting line of research on cell death in PD is focusing on the role of inflammation. Inflammatory responses occur in the brain during disease and after many types of injury. Studies in the last decade have shown that inflammation is common to a variety of neurodegenerative diseases, including PD, Alzheimer's disease, HIV-1 associated dementia, and amyotrophic lateral sclerosis. The inflammation in these diseases involves activation of microglia — specialized support cells in the brain that produce immune system signaling chemicals called cytokines. Several studies by Columbia University scientists have implicated pro-inflammatory molecules in cell death following MPTP treatment. Inhibiting the inflammatory response with drugs or by genetic engineering prevented some of the neuronal degeneration that normally occurs with MPTP treatment.

Although inflammation can be damaging, studies have shown that activating immune cells in specific ways also can protect nerve cells in animal models of spinal cord and brain injury. Recently, researchers at the University of Nebraska Medical Center and at the Columbia University Udall Center in New York successfully reduced the amount of neurodegeneration in a mouse model for PD by using an experimental vaccine to modify the behavior of microglia in the brain.

Research at the Columbia University Udall Center has shown that dopamine neurons in brains from patients with PD have higher levels of an inflammatory enzyme called COX-2 than those of people without PD. COX-2 triggers inflammation in damaged tissues. The scientists also found elevated levels of COX-2 in a mouse model for PD. When they gave these mice a drug called rofecoxib that inhibits COX-2, it doubled the number of neurons that survived. Surprisingly, however, the researchers did not find reduced inflammation with this drug. Instead, they found that the COX-2 inhibitor may protect neurons by preventing oxidative stress.

Other studies suggest that the protein GSTO-1, which has been linked to the age of onset of PD, may modify the inflammatory cytokine interleukin-1 beta and therefore may reduce the inflammation found in brains from people with PD. It also may protect against programmed cell death.

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Models for Parkinson's Disease

Much of the research that is leading to advances in understanding and treating PD would not be possible without research models – cell lines and animals with features that mimic those of

human PD. Scientists use these models to investigate questions such as what goes wrong in PD, how does cellular damage lead to behavioral symptoms, and how might potential new treatments affect the disease process. For example, levodopa, the drug most commonly used to treat PD, was shown to counteract PD symptoms in an animal model before it was tested in humans.

Researchers at the Udall Centers and other institutions are continually refining existing research models and developing new ones. Current models range from specialized, hybrid cells in culture dishes to rats and other animals with the same genetic defects identified in humans with PD. These models fall into three categories:; toxin-induced models that show how environmental factors trigger parkinsonian symptoms, genetic models that show how gene defects can affect the brain, and spontaneously occurring models that mimic some of the features of PD. The cellular and behavioral changes in toxin-induced models often overlap with those that have gene defects, providing further evidence that PD results from both environmental and genetic factors.

• Toxin-Induced Models

The two best-known and widely used animal models in PD research are the MPTP model and the 6-hydroxydopamine model. MPTP is a toxin that kills neurons in the substantia nigra, causing symptoms that closely resemble PD. Investigators discovered this reaction in the 1980s when heroin addicts in California who had taken a street drug contaminated with MPTP developed severe parkinsonism. This discovery allowed researchers to simulate PD in animals for the first time

6-Hydroxydopamine is another toxin that kills dopamine neurons, producing neuron death and parkinsonian symptoms in rats and mice. The 6-hydroxydopamine model has been used to evaluate potential PD therapies such as cell transplantation and neurotrophic factors.

In the late 1990s, researchers at the Emory University Udall Center developed a new model using a pesticide and herbicide called rotenone. ; Rotenone interferes with the activity of mitochondrial complex I. The rotenone model is the first one that produces selective neuron degeneration, Lewy bodies, and behavioral changes similar to those seen in humans with PD. Rats exposed to rotenone develop large inclusions in substantia nigra neurons that resemble Lewy bodies and contain alpha-synuclein and ubiquitin. Rotenone-treated animals also develop bradykinesia, rigidity, and gait problems.

A common theme among the toxin-induced Parkinson models is that the toxins interfere with activities of mitochondria. This knowledge has helped researchers develop additional models using different agents that act on mitochondria. For example, scientists have developed new rodent models by administering the pesticides paraquat and maneb, and by using a combination of MPTP and the drug probenecid.

• Genetic Models

The discoveries of genetic mutations in some hereditary cases of PD have prompted the development of mouse models genetically engineered to have mutations or deletions of PD genes. These so-called transgenic mice have become excellent models to study how PD develops. Genetic engineering has also been used to develop cell lines that model some of the processes that go awry in PD.

One example of a genetic model — human neuronal cells that contain mutant alpha-synuclein — was developed by researchers at the Mayo Clinic Udall Center. These cells develop levels of alpha-synuclein 25- to 50-fold higher than in controls. When these cells are exposed to rotenone, unusual forms of synuclein begin to appear.

Researchers at the University of Virginia Udall Center have developed hybrid cells, called cybrids, that have mitochondrial DNA from PD patients inserted into tumor cells. These cybrids develop

Lewy bodies just like those in the dopamine neurons of PD patients. Before this model was developed, researchers needed brain samples from PD patients in order to study Lewy bodies.

Researchers also have developed strains of mice with mutations in the alpha-synuclein and parkin genes. Mice with alpha-synuclein mutations develop an adult-onset neurodegenerative disease characterized by movement dysfunction and pathological aggregation of alpha-synuclein. Mice without the parkin gene show abnormal regulation of dopamine in the striatum and impairments in behavioral tests that require muscle coordination. Researchers are now working to develop animal models without normal DJ-1 function.

• Spontaneously Occurring Models

Scientists have identified two spontaneously occurring strains of mice that may be useful as models for PD. The first strain is known as reeler mice. These mice have reduced dopamine activity in the striatum and several other brain areas, which results in an impaired gait. The second spontaneous mouse model for PD is called the quaking mouse because it develops tremors soon after birth. Due to a chromosomal deletion, these mice lack both the parkin gene and the PACRG gene. Unlike humans with parkin deletions, this mouse does not have a loss of dopamine-producing neurons or a buildup of alpha-synuclein. However, it may help investigators understand the function of the parkin protein.

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Therapeutic Approaches

While levodopa and other drugs can provide initial relief from parkinsonian symptoms, none of these treatments halts the loss of dopamine neurons and nerve fibers. Thus, new treatments that slow the underlying disease are desperately needed. As knowledge about this disorder grows, potential new ways of preventing and treating the disease are being revealed. Promising treatments in development include new drug therapies (including neurotrophins, neuroprotectants, and immunotherapy), surgical therapies, cell transplantation, gene therapy, and transcranial magnetic stimulation.

• Drug Therapy

Current treatment for PD relies primarily on drugs to control the symptoms. While these drugs work well early in PD, they progressively fail as more nerve cells die. Drug-induced dyskinesias and fluctuations of motor symptoms also limit drug benefits in many cases.

Neurotrophic factors – molecules that support survival, growth, and development of brain cells – are one focus of new drug research. These chemicals are being studied as potential therapies for many neurological diseases. Researchers are investigating whether neurotrophic factors can halt dopamine cell degeneration and help to repair brain cells in PD. One such drug, glial cell line-derived neurotrophic factor (GDNF), has been shown to protect dopamine neurons and to promote their survival in models of PD. Researchers at the University of Kentucky Udall Center have helped to develop a technique for delivering these molecules directly into the brain. When GDNF was given for a period of 3 to 6 months, it prompted repair of dopamine neurons and improvement in their function. It also seemed to protect damaged dopamine cells from further degeneration. The researchers are now conducting an FDA-approved Phase I dose-escalation trial of chronic GDNF administration in ten patients with advanced PD at the University of Kentucky Medical Center. The investigators also are studying the mechanisms by which neurotrophic factors affect the function of dopamine neurons and the long-term effects of these proteins on brain systems. Another clinical trial in the United Kingdom used tiny pumps implanted under the skin to deliver GDNF and has shown promising initial results.

GDNF is one of a family of compounds called neurotrophins or nerve growth factors. Many of these neurotrophins are potential therapies for PD. Examples include neurotrophin-4 (NT-4),

brain-derived neurotrophic factor (BDNF), and fibroblast growth factor 2 (FGF-2). One study has shown that GDNF and NT-4 can protect dopamine neurons in culture from oxidative stress. Studies in mice have shown that BDNF can increase the number of dopamine receptors produced by brain cells. This may increase the brain's responsiveness to dopamine. Other studies have shown that BDNF protects dopamine neurons from damage in the 6-hydroxydopamine rat model for PD. FGF-2 is essential for the long-term survival of dopamine neurons, and impaired FGF-2 function may be a common underlying cause of the neuronal degeneration in PD. FGF-2 also stimulates the survival of dopamine neurons when they are transplanted into the brain.

Another developing area of PD drug research is neuroprotection – finding ways to prevent the ongoing degeneration of dopamine neurons that is a hallmark of PD. In 2002, a multicenter clinical trial suggested that a compound called coenzyme Q10 (also known as ubiquinone), which is believed to improve mitochondrial function, can slow the rate of deterioration in PD. Another early clinical trial tested a compound called GPI-1485, which acts as a neurotrophin, and found that it was well-tolerated and appeared to slow the loss of dopamine nerve terminals. A third drug, creatine, which affects mitochondrial function and acts as an antioxidant, prevents MPTP-induced neuronal damage in rats.

Investigators at the Harvard University Medical School and McLean Hospital Udall Center, along with other researchers, have identified genes that are neuroprotective in a variety of systems, from cell culture to primate models of PD. Increasing the expression of these genes, or mimicking their function with drugs, may be a new way to prevent brain damage in PD.

Therapies that change how the immune system reacts also may protect nerve cells in PD. For example, animal studies of the antibiotic minocycline, which has been used in humans for decades, have shown that it has anti-inflammatory effects in the brain and that it may prevent programmed cell death. In another study, researchers at the University of Nebraska Medical Center and the Columbia University Udall Center in New York have shown that an experimental vaccine using a drug called copolymer-1 can modify the behavior of supporting (glial) cells in the brain so that their responses are beneficial to the nervous system rather than harmful. The vaccine reduced the amount of neurodegeneration in a mouse model for PD. Another study by neurologists at the Columbia University Udall Center has shown that a drug called rofecoxib, which inhibits an inflammatory enzyme called COX-2, prevents about half of the dopamine neuron death in a mouse model for PD.

NINDS is now supporting a series of pilot clinical trials to test the effects of four of these potential neuroprotectants — coenzyme Q10, GPI-1485, creatine, and minocycline — in people with early, untreated PD (see the sidebar Neuroprotection). This series of clinical trials is called Neuroprotection Exploratory Trials in Parkinson's Disease (NET-PD). NINDS is also supporting a network of Parkinson's Disease Neuroprotection Clinical Centers to study these and other potential neuroprotectant drugs.

A variety of other compounds have been tested as potential therapies for PD. Some studies have found that proteins called alpha-2 adrenergic receptors play a role in the dyskinesias that commonly develop in PD patients treated with levodopa. Blocking these receptors has been successful in reducing dyskinesia in animal models of PD. An alpha-2 adrenergic receptor blocker called JP-1730 is now being studied in an NINDS-sponsored clinical trial to determine if it is safe and effective against dyskinesia and/or other PD symptoms. Another drug, levetiracetam, is also being tested in a controlled clinical trial to see if it can reduce dyskinesias in Parkinson's patients without interfering with other PD drugs. Levetiracetam, which is approved by the FDA to treat epilepsy, is not an alpha-2 adrenergic receptor blocker. Instead, researchers believe it may work by interfering with the neurotransmitter GABA (gamma-amino butyric acid).

Another clinical trial is studying GM1 ganglioside, a chemical which contributes to cell growth, development, and repair, to determine if this drug can improve symptoms, delay disease progression, and/or partially restore damaged brain cells in PD patients. Preliminary studies have shown beneficial effects of this drug on the dopamine system in animal models.

Several chemicals are being tested as potential treatments for the mood disorders that sometimes occur in people with PD. One clinical trial is investigating whether a drug called quetiapine can help to reduce psychosis and/or agitation in PD patients with dementia, and in dementia patients with parkinsonian symptoms. Another clinical study is examining whether s-adenosyl-methionine (SAM-e), a food supplement that improves dopamine transmission, can help to alleviate depression in patients with PD.

A number of clinical studies have suggested that cholinesterase inhibitors, which are commonly used for Alzheimer's disease, can also have a positive effect on cognition, psychiatric symptoms, and global function in patients with PD plus dementia. Additional clinical studies are now underway.

• Surgical Therapies

Surgical treatments for PD, especially pallidotomy and deep brain stimulation (DBS), are important options for improving the lives of people affected by this disease. Investigators are continuing to evaluate these procedures in patients.NINDS is supporting a great deal of research about DBS, including studies that aim to improve the technology for DBS and a large-scale clinical trial done in collaboration with the Department of Veterans Affairs that compares DBS to the best medical management with drugs. Investigators are studying normal brain circuits in order to find the best placement for the electrodes in the brain and the best stimulation patterns for DBS. In addition, they are working to develop a screening tool to identify PD patients who will get the most benefit from DBS.

• Cell Transplants

Cell replacement through transplantation is an; emerging approach for repairing the damage PD causes in the brain. Many; researchers are working to develop cell transplantation therapies. In; addition to embryonic stem cells, which have the potential to become any kind; of cell in the body, researchers are experimenting with adult neural stem; cells, neural precursor cells, and fetal-derived dopamine-producing; neurons. Even cells derived from non-neuronal tissue are being; considered for PD research.

However, very little is known about these; different types of cells, and researchers need to better understand the; fundamental biology of stem cells and neural precursor cells before such; technologies can be used to treat PD in a safe, effective, and predictable; manner.

In several early clinical studies, grafting of; fetal-derived dopamine tissue led to an increase in dopamine production in the; brains of people with advanced PD. Unfortunately, these studies showed few; long-term benefits and led to unanticipated side effects such as dyskinesias. These problems preclude widespread use of this particular approach.

Investigators at the Harvard University; Medical School and McLean Hospital Udall Center have injected mouse embryonic; stem cells directly into the rat brain and found that these cells can develop; into dopamine neurons. They also have shown that they can generate; dopamine neurons from rodent embryonic stem cells. They are now testing; primate and human embryonic stem cells in animal models of PD with a goal of; moving this therapy into human clinical trials.

Some researchers have found that muscle progenitor; cells isolated from the muscle of adult rats can be induced to form cells with; neuron-like properties. Although it is unclear whether these cells can; actually function like neurons, this finding raises the possibility that; muscle tissue may be a source of progenitor cells to treat diseases of the; nervous system. In another study, researchers transplanted dopamine-producing; brain cells from pigs into the brains of PD patients and found some evidence; of clinical improvements. The immune systems of these patients had to be; suppressed so that the grafted pig cells would not be; rejected.

Yet another transplantation approach employs retinal pigment epithelial cells, which produce dopamine and can be cultivated in large numbers. These cells are attached to microscopic gelatin beads and implanted into the brains of PD patients as part of a clinical trial to determine if they can enhance brain levels of dopamine and thus reduce the symptoms of PD.

One of the key problems with stem cell transplantation is to control and manage

how the cells become dopamine-producing neurons. Recently, investigators found that genetically engineering mouse embryonic stem cells to produce a protein called Nurr1 led to a four- to five-fold increase in the number of dopamine neurons produced in culture. Nurr1 also enhanced the neurons' ability to produce and release dopamine. The identification of this important factor in dopamine neuron development paves the way for new therapies that require management of stem cell differentiation.

Other studies have shown that embryonic stem cells also form dopamine cells if they are transplanted directly into the brain and that these cells can reduce motor dysfunction and normalize dopamine production in an animal model of PD. A low cell concentration of embryonic stem cells increases the influence of the host brain, increasing the number of dopamine cells produced and reducing the likelihood that the stem cells will develop into tumors.

Researchers at NINDS are studying signals that control the proliferation and differentiation of stem cells. Along with other researchers, they have shown that stem cells can generate nerve cells that are capable of establishing connections (synapses) with other neurons. They also have shown that mouse embryonic stem cells can be manipulated to generate central nervous system stem cells.

The NIH has established an NIH Stem Cell Unit to help characterize stem cells for future clinical use and to learn how to control differentiation in federally approved stem cell lines.

• Gene Therapy

Gene therapy offers great potential for PD and many other brain disorders. With this type of therapy, viruses are engineered to deliver genes that increase the supply of dopamine, prevent cell death, or promote regeneration of neurons. Although this approach is promising, researchers need to develop efficient and safe means to deliver genes to brain cells in order for gene therapy to be used in humans. Many researchers are working to develop better viral vectors – viruses that can carry genes into the targeted cells – and to find ways of improving the transfer of these vectors to the brain. As researchers accumulate more information about the safety and efficacy of different delivery systems, research on gene therapy for PD can move forward.

The NINDS is supporting a consortium called the Parkinson's Disease Gene Therapy Study Group, which is investigating dopaminergic enzyme gene therapy and neurotrophic gene therapy in animal models of PD. This consortium includes many Parkinson's experts from research centers across the country. The investigators are comparing different genes and testing different gene delivery approaches. As part of this project, researchers at Northwestern University in Illinois have developed a viral gene vector with a special modification that allows the introduced gene to be temporarily “turned off” when the patient is given a small dose of a specific antibiotic. The development of this vector should permit researchers to better control the delivery of genes once the vector is in the host. The researchers are now conducting safety and toxicity studies of this new vector with the hope that it will prove safe enough for testing in humans.NINDS-funded investigators have found that using a genetically modified virus to deliver specific growth factors to primates with a parkinsonian condition leads to dramatic improvements in symptoms. Another group of researchers has shown that engineering a virus to deliver enzymes important for the production of levodopa can have beneficial effects in a rat model of PD.

Investigators also are experimenting with the gene for 1-amino acid decarboxylase (AADC), an enzyme that converts levodopa into dopamine. Research in animal models has shown that

neurons in the striatum can be given the AADC gene using a viral vector, causing them to convert levodopa to dopamine. This essentially mimics the function of the dopamine neurons that are lost in PD and may reduce the need for drugs that increase the level of dopamine in the brain.

Researchers also are experimenting with gene therapy to deliver the GDNF gene to the brain. In a monkey model, GDNF prevented dopamine neurons from dying, and the monkeys regained some of their lost motor skills.

• Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) is a technique that uses an insulated wire coil placed on the scalp to create a magnetic pulse that stimulates the brain. Investigators at NINDS are conducting clinical studies of TMS and a related technique called transcranial electrical polarization to learn if they might have beneficial effects for people with PD. Studies have suggested that these techniques might be able to alter brain circuits in beneficial ways. Some studies of TMS have shown small effects on bradykinesia. TMS also may be able to produce beneficial effects on gait and freezing.

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Other Clinical Research

While many clinical studies are investigating potential new treatments, clinical research also can help to reveal better ways of diagnosing and tracking PD.

In a series of studies, intramural researchers at NINDS have found evidence that PD causes widespread damage to the sympathetic nervous system, in addition to the substantia nigra. The sympathetic nervous system controls functions such as blood pressure and heart rate. Individuals with PD often experience symptoms such as orthostatic hypotension, or a drop in blood pressure upon standing, and the loss of sympathetic nerves observed in this study may help to explain why this occurs.

In another study, researchers at the Columbia University Udall Center have developed a method to track the progression of PD in patients at early stages of the disease using PET imaging techniques. These techniques allow the researchers to examine dopamine transporter binding, a measure of dopamine levels, in the brains of people with PD and in healthy individuals. They have found that the onset of motor symptoms in people with PD is accompanied by a 70 percent loss of dopamine in the brain. They also studied how DBS changes activity in the brain. PET imaging of PD patients shows hyperactivity in some brain regions prior to treatment, probably resulting from the loss of dopamine. DBS suppresses this hyperactivity. The stimulation also was accompanied by improvement in motor function. This study helped to reveal how DBS may improve symptoms in PD.

Some investigators are using neuroimaging of dopamine and other chemicals in the brain to assess how the brain functions during cognition, sleep, and activity, and how DBS changes these functions. Another NINDS-sponsored clinical study is using single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) to examine the brain's nicotine receptors, which respond to the neurotransmitter acetylcholine. Previous studies have shown changes in the acetylcholine system in PD patients. These changes tend to be more pronounced in patients with dementia. The current study should clarify how acetylcholine interacts with other neurotransmitters in people with PD, and may lead to new ways of diagnosing or treating the disease.

Other researchers are assessing quality of life in patients with PD and other neurological conditions and working to develop a global statistical test for diagnosing PD.

Another important area of research aims to improve rehabilitation and assistive technology for people with PD. This research includes studies of ways to improve posture and movement in people after they have been treated with DBS, studies on the effects of exercise, studies of voice training, and development of an assistive device for people with vocal impairment. Other studies are focusing on treatments for cognitive impairment, memory problems, urinary tract dysfunction, sleep disorders, and micrographia (abnormally small handwriting due to difficulty with fine motor control).

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Conclusion and Future Directions

While Parkinson's is a complex disease, research has progressed a great deal in recent years. Halting the progression of PD, restoring lost function, and even preventing the disease are now considered realistic goals. Much of the recent progress has been funded by the NINDS through the Udall Parkinson's Disease Research Centers of Excellence and many other grants. Researchers have identified many susceptibility genes and potential environmental risk factors for PD, and these studies are contributing to a much-improved understanding of how PD develops. A number of promising therapies have been developed as a result of this understanding and are now being tested in humans and in animal models. Continuing studies to improve understanding of the underlying biology of the disease will lead to better ways of relieving the symptoms of Parkinson's patients and ultimately preventing or halting the disease.

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Sidebar: Morris K. Udall Centers of Excellence for Parkinson's Disease ResearchOverview

As part of its efforts to defeat PD, the NINDS supports a number of Centers of Excellence for Parkinson's Disease Research throughout the country. The Centers' multidisciplinary research environment allows scientists to take advantage of new discoveries in the basic and technological sciences that can lead to clinical advances, and, in addition, allows for collaborations across centers which can expedite the pace of research. Most of the Centers also provide state-of-the-art training for young scientists who are preparing for research careers investigating PD and related neurological disorders. Some of the topics that the Centers address include:

Neuronal and mitochondrial genetic studies to elucidate key proteins involved in neurodegeneration and to determine genetic differences between familial and sporadic PD

Studies of the structure and function of proteins involved in cell death and degeneration

Studies of the anatomical structures and brain chemicals involved in PD

Studies to improve animal models of PD

Imaging studies involving PET

Studies of PD risk factors in people of different gender and ethnicity

Animal studies testing possible PD treatments, such as neuroprotective therapies, implantation of genetically engineered cells, DBS, and levodopa drug therapy.

These Centers have contributed greatly to the PD research field. Their many significant achievements include discovery of the UCH-L1, PACRG, and GSTO-1 genes, development of the rotenone rat model for PD, the discovery that PD mitochondrial gene expression is sufficient to spontaneously cause development of Lewy bodies in cells, and the first United States clinical trial of chronic GDNF administration in patients with advanced PD.

Recently, the NINDS has funded a Parkinson's Disease Data Organizing Center (PD-DOC) to collect information from all PD centers, thus allowing for standardized data, resources, and reagents to be shared widely within the PD community. The NINDS hopes that research at these Centers of Excellence will lead to clinical trials of new treatments in patients with PD.

History

On November 13, 1997, the President of the United States signed into law The Morris K. Udall Parkinson's Disease Research Act (P.L. 105-78). Prior to the passage of this Act, the NINDS had already recognized the need to establish Centers of Excellence in PD research, and as a result, released an initial Request for Applications (RFA) to solicit these centers. Of the applications that were received in response to this RFA, NINDS selected three centers for funding. Following the passage of the Udall Act, NINDS issued a second RFA for PD Centers of Excellence and funded eight additional grants. All of the Udall Centers focus on scientific research designed to improve the diagnosis and treatment of patients with PD and related neurodegenerative disorders and on research to gain a better understanding of the fundamental cause(s) of the disease. The Centers have lived up to their expectation to foster an environment that enhances the research effectiveness of investigators in a multidisciplinary setting, utilizing specialized methods relevant to the study of these disorders.

The Centers of Excellence for Parkinson's Disease Research program was developed in honor of former Congressman Morris K. Udall, who died in 1998 after a long battle with PD. Mr. Udall was elected to the U.S. House of Representatives in 1961 in a special election to replace his brother Stewart who left the position to become President John F. Kennedy's Secretary of the Interior. Udall was diagnosed with PD in 1979, but he remained active as a Member of Congress until May 1991.

Future

NINDS is committed to continuing and enhancing the tradition of scientific excellence that has been fostered by the Udall Centers over the past 5 years. To this end, NINDS and the National Institute of Environmental Health Sciences released a Program Announcement in October 2002 to renew the Institute's commitment to the program and to aid current and prospective Udall Center investigators in developing competitive applications for funding. NINDS has also announced an increase in funds that may be allotted to the Centers to fund the types of clinical research needed to capitalize on the increasing number of findings in the basic sciences. In addition, NINDS staff members are working with the research community to develop a standard, minimum amount of clinical information to be collected about each PD patient, allowing information from different studies to be compared and combined. NINDS believes that all of these efforts will help to strengthen the Udall program in the coming years.

Udall Centers Across the Country

Brigham and Women's HospitalBoston, MassachusettsDirector: Peter Lansbury, Jr., Ph.D.

Columbia UniversityNew York City, New YorkDirector: Robert Burke, M.D.

Duke UniversityDurham, North CarolinaDirector: Jeffery M. Vance, M.D.

Harvard University Medical School;and McLean HospitalBelmont, MassachusettsDirector: Ole Isacson, M.D.

Johns Hopkins University School of MedicineBaltimore, MarylandDirector: Ted M. Dawson, M.D., Ph.D.

Massachusetts General Hospital;and Massachusetts Institute of TechnologyBoston, MassachusettsDirector: Anne Young, M.D., Ph.D.

Mayo ClinicJacksonville, FloridaDirector: Dennis W. Dickson, M.D.

Northwestern UniversityChicago, IllinoisDirector: D. James Surmeier, Ph.D.

University of California, Los AngelesLos Angeles, CaliforniaDirector: Marie-Francoise S. Chesselet, M.D.

University of KentuckyLexington, KentuckyDirector: Greg A. Gerhardt, Ph.D.

University of PittsburghPittsburgh, PennsylvaniaDirector: Michael J. Zigmond, Ph.D.

University of VirginiaCharlottesville, VirginiaDirector: G. Fred Wooten, M.D.

Coordinating data and resources from all these centers:

Parkinson's Disease Organizing CenterUniversity of RochesterRochester, New YorkDirector: Roger Kurlan, M.D.

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Sidebar: Deep Brain Stimulation

For many years, the only surgical treatments for PD were pallidotomy and thalamotomy – procedures in which surgeons selectively destroy small portions of the brain in order to relieve tremor and rigidity. The tissue destruction is irreversible. Because these procedures often led to troubling side effects, surgery was largely replaced with drug therapy once levodopa became available for PD in the 1960s.

In the 1980s, researchers in France discovered that chronic stimulation (now termed deep brain stimulation or DBS) of a brain region called the thalamus could block tremors in patients with essential tremor. Studies in a monkey model for PD also revealed the brain circuits that are altered in this disease and pointed to a brain region called the subthalamic nucleus as a key

target. This discovery opened the door to a new era of surgical treatments. Investigators then examined the effects of stimulating the subthalamic nucleus in patients with PD and found that the stimulation had; profound effects on patients' tremor, slowness, and stiffness. In DBS, electrodes are implanted into the brain and connected to a small electrical device called a pulse generator that can be externally programmed. DBS reduces the need for levodopa and related drugs, which in turn decreases the involuntary movements called dyskinesias that are a common side effect of levodopa. It also helps to alleviate fluctuations of symptoms and to reduce tremors, slowness of movements, and gait problems. Unlike pallidotomy and thalamotomy, DBS is reversible. However, it requires careful programming of the stimulator device in order to work correctly.

DBS has now been approved by the U.S. Food and Drug Administration, and it is widely used as a treatment for PD. It also is used to treat dystonia and essential tremor, and it is being tested for disorders such as Tourette syndrome, epilepsy, and depression. Researchers are continuing to study DBS and to develop ways of improving it. They are conducting clinical studies to determine the best part of the brain to receive stimulation and to determine the long-term effects of this therapy. They also are working to improve the technology available for DBS.

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Sidebar: Gene Discoveries

One of the most dramatic changes in PD research in the past decade has been the emergence of genetics as a major tool for understanding the disease. Until the mid-1990s, most researchers believed that PD was caused solely by environmental factors. However, researchers at the UMDNJ-Robert Wood Johnson Medical School in New Jersey had identified an Italian family with what appeared to be an inherited form of PD. In 1995, they began to collaborate with researchers at the National Human Genome Research Institute (NHGRI), who analyzed DNA from these patients. Within a few years, the NHGRI researchers had traced the disease in this family to a mutation in the alpha-synuclein gene. Investigators soon identified alpha-synuclein mutations in several other families as well.

These findings touched off an explosion of work on the function of alpha-synuclein as well as intensive searches for other PD genes. Researchers soon discovered that alpha-synuclein is a major component of Lewy bodies, suggesting that it might play a role in sporadic forms of the disease as well as inherited ones. They also located four more PD genes – parkin, DJ-1, DRDN, and PINK1 – and several other genes that appear to influence the disease, although their role is not yet clear. In 2003, investigators at the National Institutes of Health and elsewhere discovered that, in one large family, a triplication of the normal alpha-synuclein gene caused the disease. The extra genes cause overproduction of alpha-synuclein, which can accumulate inside brain cells.

Together, these studies have dramatically changed researchers' understanding of how PD develops. Hundreds of investigators are now looking for additional PD genes and studying how the proteins produced by these genes affect cells. Others are examining how genes and environmental factors may interact to produce the disease. These studies may lead to vastly improved treatments for the disease, or possibly even ways of preventing it.

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Sidebar: Neuroprotection

A major goal of PD research is the development of new therapies. Currently available treatments for PD can effectively control motor symptoms of the disease in the early stages, but they don't slow or halt the relentless progression of the disease. An explosion of discoveries during the past decade is now providing renewed hope of a therapy that will prevent the underlying nerve damage in this disease – a strategy known as neuroprotection.

The idea of neuroprotection for PD is not new. A number of clinical studies have tested different compounds to see if they might stop the disease progression. Some studies initially showed small positive effects, but most of these studies included a limited number of patients and did not examine the effects of these therapies over a long period of time. In addition, researchers have no good way of measuring whether these or other compounds truly prevent neuronal damage. Consequently, researchers cannot be sure that the positive effects seen in these studies are due to neuroprotection or if they represent short-term effects on symptoms.

Recently, a wealth of new information about how neurons may be damaged in PD has allowed investigators to identify many potential new ways of treating this disease, including nerve growth factors, anti-inflammatory drugs, and antioxidants. To overcome some of the problems that have plagued previous studies, in 2002 an NINDS-sponsored committee conducted a systematic review of data on 59 potential neuroprotective agents for PD. This committee ultimately selected four of the most promising drugs for study in a series of clinical trials known as Neuroprotection Exploratory Trials in Parkinson's Disease (NET-PD). These drugs — coenzyme Q10, GPI-1485, creatine, and minocycline — are now being tested at more than 40 centers in the United States and Canada. Researchers hope that this new approach to selecting and testing compounds will lead to the first proven neuroprotective therapy or therapies for PD and revolutionize treatment of this disease.

"Parkinson's Disease: Challenges, Progress, and Promise", NINDS. December 2004.

NIH Publication No. 05-5595

Back to Parkinson's Disease Information Page.

Prepared by:Office of Communications and Public LiaisonNational Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesda, MD 20892

NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke or any other Federal agency. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient's medical history.

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