parkinson‘s disease treatment and models. definition parkinson‘s disease (pd) is the second most...
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PARKINSON‘S DISEASE
Treatment and models
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DEFIN
ITIO
NDEFIN
ITIO
N• Parkinson‘s disease (PD) is the second
most common neurodegenerative disorder after Alzheimer‘s disease.
• It is characterized by the loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons.
• Parkinson is affecting 1% of the population older than 50 years.
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DEFIN
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NDEFIN
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N• Characteristic are also the presence
of intraneuronal cytoplasmic inclusions, called Lewy Bodies (LBs).
• PD is also called Paralysis agitans and Shaking palsy because it causes resting tremor, muscular rigidity and the loss of postural reflexes.
• The sense and intellect remains quite normal.
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DOPAMIN
EDOPAMIN
E• Is a neurotransmitter in the
substantia nigra, caudate nucleus and putamen (basalganglia)
• It is essential for a normal movement and transmit the signal between cortex and thalamus.
Neocortex
Basalganglia
Thalamus
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Development:
Dopa Dopamine + CO2
• MAO and COMT destroy Dopamine.
• Dopamine cannot cross blood-brain-barrier.
DOPAMIN
EDOPAMIN
E
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Bra
in-b
loo
d-b
arri
erB
rain
-blo
od
-bar
rier
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2 forms:αα
-SY
NU
CL
EIN
-SY
NU
CL
EIN α-syn:
• Is a 140 amino acid protein, very abundant in the brain.
• its exact function is not known yet.
• It has a natural tendency to clump together to form insoluble aggregates (LBs, LNs) and this tendency is likely increased in the mutated form.
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αα-S
YN
UC
LE
IN-S
YN
UC
LE
IN• Detected immunohistochemically in
LBs, LNs. (LB Dementia, Parkinson‘s, Alzheimer‘s, NBIA1).
• In Drosophila: similar perinuclear and neuritic filamentous inclusions like LBs & LNs.
• Is the precursor protein of a nonamyloid-β-protein component (NAC) isolated from Alzheimer‘s plaques.
• Induces selective and progressive loss of DA neurons.
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ββ-S
YN
UC
LE
IN-S
YN
UC
LE
INβ-syn: homologue to α-syn
• Is not able to form insoluble LBs or LNs.
• Aminoacids 73-83 in the NAC region are absent
= nonamyloidogenic
• This region (aa 73-83) is essential for This region (aa 73-83) is essential for the typical aggregations in the brain.the typical aggregations in the brain.
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Selective Insolubility of Selective Insolubility of αα-syn in -syn in human Lewy Body diseaseshuman Lewy Body diseases
Lewy Body diseases:
- Parkinson‘s Disease
- Alzheimer‘s Disease
- LB Dementias
- Hallervorden – Spatz Disease (NBIA type1)
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Transgenic mice expressing human Transgenic mice expressing human
αα-syn-syn
Wild type: [wt]
Point mutation: [A30P]- α-syn
Point mutation: [A53T]- α-syn
Promotor: THY1 (brain neuron-specific)
Investigation of solubility of „syns“ in human LB Diseases
transgenic animals expressing human [wt] and mutant [A30P]- α-syn,
[A53T]- α-syn
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IMP
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ION • [wt] and mutant α-syn assembled into LB-like
fibrils in transgenic Drosophila:
locomotor deficit became apparent with increasing age.
2 missense mutations in the α-syn gene (rare) dominantly inherited PD.
• In transgenic mice:
somal and neuritic accumulations of [wt] and mutant α-syn were observed in transgenice mouse brain.
modest reduction of locomotor performance, due to age-dependent degeneration of neuromuscular junctions.
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IMP
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ION α-syn and β-syn: both in synaptosomal
fractions of rodent + human brain.
• α-syn: highly soluble in aqueous buffer
In case of LB diseases:
detergent- insoluble α-syn + aggregates
were found in urea extracts.
Human α-syn was detergent-insoluble in
transgenic mouse brains, but not
endogenous mouse α-syn and β-syn!
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IMP
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ION • β-syn: no aggregates in vitro (no 73-83)
Conclusion:Conclusion: specific accumulation of
detergent-insoluble α-syn in transgenic
mice recapitulates a pivotal feature of
human LB diseases.
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• Antibodies (rat, mouse) against LB recognizing epitopes
• Brain fractionating and Western Bloting• Generation and Characterization of
transgenic mice• In vitro aggregation
of recombinant syns
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• Drosophila:Drosophila:– short generation time– fully sequenced genome– vast array of genetic information– availability of huge number of stocks
containing mutations in almost every genes
Complete control about the experiment
– short life-span: investigations of age-dependent disorders (neurodegeneration)
– expression of human α-syn-gene causes several characteristics of human PD:
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Late-onset progressive degeneration of subsets of DA neurons.
Develop filamentous protein aggregates rich in α-synuclein within cell bodies and neurites of DA neurons.
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• Heat shock proteins • Up-regulated during stress response• Help to refold misfolded proteins
Auluck et al. – aggregation = disorder involving
protein misfolding.
Boost the amount of chaperones in neurons
• Expression of gene encoding human Hsp70 completely prevents late-onset loss of DA neurons (induced by human α-syn).
• Decreasing endogenous chaperone activity accelerates the neuronal loss in PD flies.
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CH
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Linkage to specific genes
Fly modelof disease
Fly genetics to develop new treatments
α-synuclein
Fly Prakinson‘s disease
Prakinson‘s disease
Treatment of Treatment of Prakinson‘s Prakinson‘s diseasedisease
Treatment Treatment of human of human diseasedisease
Chaperones
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• Polyglutamine disease: same neuronal
degeneration (expanded polyglutamine stretches)• Abnormal polyglutamine proteins suppressed by
Hsp70
Coexpression of Hsp70 with α-syn • Normal numbers of DA neurons in aged flies
control: β-galactosidase coexpressed with α-syn • 50% loss of DA neurons in aged flies
(α-syn – concentration did not alter [immunoblot] )
Interaction between endogenous chaperone Interaction between endogenous chaperone activity and activity and αα-synuclein.-synuclein.
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Influencing of α-syn confirmation? α-syn interferes with chaperone‘s activity by
sequestration?
• Chaperones can „detoxify“ the protein aggregation in a more subtle way.
• Risk factors may hamper normal activity of chaperones (smoking)
• Inducing general stress response: (for treatment)Increases production of chaperonesAdvertantly protect neurons?
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Main goal:Main goal: increase dopamine level
• Dopamine precursors: can cross blood-brain-barrier, changed to dopamine– i.e. Levodopa, Sinemet, Madopar
• Dopamine agonists: act directly on dopamine receptors (D1, D2), replace dopamine– i.e. Apomorphine, Mirapex
• Inhibitors of dopamine metabolism:– i.e. Selegiline, Eldepryl
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• Blocking the reuptake of dopamine/ increasing the release of dopamine: – i.e. Symmetrel
• COMT inhibitors (Catechol-O-methyltransferase): are taken with L-Dopa, slow the break down of it. – i.e. tolcapone, entacapone
• Anticholinergics: act not directly on dopamine, help to decrease the activity of Ach, which is balancing neurotransmitter– i.e. trihexyphenidyl
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• Pallidotomy: tiny hole drilled in the skull, electric probe is used to destroy a small part of the global pallidus to reduce dyskinesia
• Deep brain stimulation (DBS): very thin electrode is implanted into the brain, small electric pulses are used to stimulate the brain , blocks signals that cause PD symptoms.
• Stem cell therapy: stem cells are undifferentiated cells, can be manipulated to differentiate into dopamine producing neurons (still experimental stage)
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Neuron developed from stem cell
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• Science #295: Auluck et al.
„Suppression of α.synuclein toxicity in a Drosophila model for Parkinson‘s disease“
• Science #295: Helfand„Chaperones take flight“
• Am J Pathol #159: Kahle et al.„Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model“
• www.allsciencestuff.com/mbiology/research/parkinsons
…