Download - lysosomes presentation
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Presenting by:
Anushree, Chaitra M.C, Swetha Chenna
WHAT HAPPENS WHEN THINGS GO WRONG IN THE
CELL?
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PLAN OF THE TALK
Introduction
Properties of lysosomes
Functions
Related diseases
Treatment
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WHEN WAS IT DISCOVERED?
Lysosomes are discovered by a Belgian cytologist, Christian René de Duve (also peroxisomes) in 1949 and won a Nobel prize.
Alex Novikoff from the University of Vermont took the first electron micrographs of the new organelle.
In Greek “lysis” means destruction or dissolution and “soma” means body.
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WHAT ARE THEY?
It is roughly spherical or elongated, single membrane bound cell organelle and the size ranges from 0.1 to 1.2μm.
They are acidic, with a pH of 4.6 favouring the enzyme activity, which is maintained by pumping protons from the cytosol that has a pH of 7.2 through proton pumps.
They enclose various soluble hydrolytic enzymes. These are also called as “suicidal bags of the cell” and
also “little stomach of the cell”. The absence of a single enzyme leads to several
disorders in humans. These are present exclusively in animal cells (in plant and
fungal cells vacuoles perform similar function).
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WHAT IS THE STRUCTURE OF THE LYSOSOME?
Glycoprotein rich membrane.
Lysosomal associated membrane proteins(lamp) and Lysosomal integral membrane proteins(limp)
Unusual lipids
lyso-bisphosphatidic acid, thought to protect lysosomal membrane lipids from action of lumenal lipases
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HOW ARE LYSOSOMES STAINED?
Staining with acridine orange.
Staining with antibodies.
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HOW LYSOSOMES ARE FORMED?
Two models for formation of lysosomes
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HOW LYSOSOMES ARE FORMED?
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pH 6-6.5
pH 5-5.5
pH 4.5-5
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HOW ENZYMES ARE TRANSPORTED INTO
THE LYSOSOMES?
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MANNOSE-6-PHOSPHATE RECEPTOR
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WHAT KIND OF ENZYMES ARE PRESENT IN
LYSOSOMES?
About 50 acid hydrolases have been found.
Acid nucleases such as ribonuclease II, deoxyribonuclease II and exonuclease hydrolyze nucleic acids to nucleosides.
Acid proteases such as cathepsin-L, cathepsin-D and carboxypeptidase-A hydrolyze proteins to amino acids and dipeptides.
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WHAT KIND OF ENZYMES ARE PRESENT IN
LYSOSOMES?
Acid glycosidases such as β-galactosidase, α-glucosidase and α-mannosidase hydrolyze polysaccharides to monosaccharides and disaccharides
Acid lipases such as phospholipase-A1 and triacylglycerol lipase hydrolyze lipids to fatty acids
Acid phosphatase hydrolyzes phosphate esters to inorganic phosphates
Arylsulfatase B hydrolyzes sulfur esters to inorganic sulfates
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HOW DOES THE LYSOSOME MAINTAIN ITS pH?
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ATP driven proton pumps in the lysosome membrane move H+ ions from the cytosol into the lumen of the lysosome, thus lowering internal pH.
V-type of Proton pumps are present in the lysosomes.
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WHAT ARE THE FUNCTIONS OF LYSOSOMES?
1. Autophagy
2. Role in endocytosis and phagocytosis
3. Role in apoptosis
4. Role in fertilization
5. Role in repairing cell membrane
6. Exocytosis(secretion)
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1. WHAT IS AUTOPHAGY?
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WHAT IS THE NEED FOR AUTOPHAGY?
Autophagy is the intra cellular process, by which cell degrades its own components using lysosomal machinery and recycles the molecules.
Damaged macromolecules, malformed proteins, non-functional, damaged and old organelles are all broken down by the lysosomal enzymes and thus, helps in the organelle turnover, that is, the regulated destruction of the cell’s own organelles and their replacement.
During starvation or nutrient-limiting conditions, autophagy of normal organelles occurs, thus helping to maintain the level of nutrients required for the normal cellular processes.
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2. WHAT IS ENDOCYTOSIS?
Endocytosis is the process for the cellular uptake of foreign material.
"Endocytosis” came from the word “endo” which means “within”, “cyt” meaning “cell” and “-osis” meaning “process”.
Types of endocytosis
A. Phagocytosis
B. Receptor-mediated endocytosis
C. Potocytosis
D. Macropinocytosis
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MULTIPLE PATHWAYS OF ENOCYTOSIS
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A. WHAT IS PHAGOCYTOSIS?
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B. WHAT IS RECEPTOR-MEDIATED
ENDOCYTOSIS?
Brings about the uptake of specific extracellular macromolecules (ligands) following their binding to receptors on the external surface of the plasma membrane.
Is an important process in exogenous antigen processing(endocytic pathway).
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ELECTRON MICROGRAPHS OF RME
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WHAT IS CLATHRIN?
Clathrin-coated vesicles are found in all eukaryotic cells.
Particularly enriched in the brain, where they play a major role in the formation of neurotransmitter-containing pre-synaptic vesicles required for synaptic nerve transmission.
Each clathrin protein molecule consists of three heavy chains and three light chains, joined together at the center to form a three-legged assembly called a triskelion.
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FORMATION OF CLATHRIN COATED
VESICLE
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ENDOCYTIC PATHWAY!
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C. POTOCYTOSIS
Potocytosis is a type of receptor-mediated endocytosis in which small molecules are transported across the plasma membrane of a cell.
The molecules are transported by caveolae(rather than clathrin-coated vesicles) and are deposited directly into the cytosol.
The ligand is usually of low molecular mass(e.g. vitamins), but some larger molecules (such as lipids) can also act as ligands
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D. WHAT IS MACROPINOCYTOSIS
Non-specific endocytosis of solute macromolecules.
It has been exploited by some pathogenic bacteria as a novel route for entry into cells.
Happens through actin-mediated membrane ruffling and blebbing.
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3. WHAT IS APOPTOSIS?
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WHAT IS THE ROLE OF LYSOSOME IN
APOPTOSIS?
Lysosomes can be used to kill cells when they are supposed to be destroyed.
some cells have to die for proper development in an organism.
ex: tadpole tail gets re-absorbed when it turns into a frog
ex: loss of webbing between your fingers during fetal development
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syndactyly
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4. WHAT IS THE ROLE OF LYSOSOMES IN
FERTILIZATION?
During fertilization, the lysosomal contents of the sperm are released outside, in order to digest the limiting membrane around the egg, thus facilitating the fusion of sperm and egg.
Also helps in degradation of paternal(sperm) mitochondria.
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5. WHAT IS THE ROLE OF LYSOSOMES IN
MEMBRANE REPAIR?
The conditions of mechanical stress and pathogenic actions leads to the disruption of patches or formation of pores in the cell membrane.
The secretory lysosomes fuses near to the damaged part of membrane and releases hydrolases outside the cell, among which a special hydrolase called acid sphingomyelinase causes the internalisation of the damaged patch.
The fusion of the lysosome with the cell membrane provides extra lipids and prevents constriction of cellular boundary.
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THE PATCH HYPOTHESIS
A. Undisturbed cell
B. A large disruption of plasma occurs
C. The accumulating vesicles begin to fuse with one another to create large patch vesicles
D. Vesicle-vesicle fusion creates more and larger patch vesicles
E. A patch of internal membrane added is thereby added
F. Post-resealing polymerization of F-actin and its contraction mediated by myosin restores subcortical network continuity. Resealing is now complete
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6. ROLE AS A SECRETORY ORGANELLE
Secretory lysosomes are a combination of conventional lysosomes and secretory granules.
These secretory lysosomes package additional secretory products, respond to extracellular stimuli and fuse with the plasma membrane to release their contents.
Secretory lysosomes are found, although not exclusively, in cells of the immune system and melanocytes.
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DO LYSOSOMES SHOW ANY SPECIFICITY
FOR PROTEIN DEGRADATION?
KFERQ standing for lysine(K), phenylalanine (F), glutamate (E), arginine (R), and glutamine (Q) that cause the proteins bearing them to be selectively delivered to lysosomes for degradation.
It is possible that the KFERQ sequences attach these proteins to cytosolic organelles that are on the way to being autophagocytosed, thereby dragging the proteins into the lysosome indirectly.
Alternatively, there may be a specific transporter in the lysosomal membrane that recognizes these signals and transfers the proteins directly across the lysosomal membrane.
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WHAT HAPPENS WHEN THINGS GO WRONG
IN THE LYSOSOMES?
Occupational Diseases: Silicosis
Material made of Silica: Rose quartz, glass, digital watches, porcelain, beach sand.
Inhaled silica (silicon dioxide) dust enters lungs
Macrophage ingest & silica dust enter secondary lysosomes
Can't be digested; affects lysosome membrane integrity
Lysis & release of enzymes
Sets up inflammatory response in lung tissue
Can lead to silicosis, tuberculosis, cancer and failure of respiratory system
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WHAT ARE LYSOSOMAL STORAGE DISEASES?
Lysosomal storage diseases (LSD’S) are characterised by the presence of abnormally enlarged lysosomes containing accumulated undigested cellular components.
The components or macromolecules that accumulate depends on the specific enzyme that is dysfunctional.
Over 50 such diseases have been described, affecting approximately 1 in 8000 infants.
very rare.
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LYSOSOMAL STORAGE DISORDERS
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SOME OF THE LIPID RELATED LSD’S
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SOME OF THE CARBOHYDRATE
RELATED LSD’S
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SOME OF THE LYSOSOMAL MEMBRANE
RELATED LSD’S
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SOME OTHER LSD’S
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TAY-SACHS DISEASE
It is an autosomal recessive disease which occurs due to deficiency of an enzyme called Hexosaminidase A (also called N-acetylglucosaminidase A).
Occurrence in Jewish People of Ashkenazic (Central European) Descent
Build up in secondary lysosomes and constrict nerve axons.
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TAY-SACHS DISEASE
SYMPTOMS: cherry red spot on
retina loss of peripheral
vision reduction in
development by age of 2 - seizures,
diminishing mental functions
loss of coordination DIAGNOSIS:
Enzyme assay for measuring Hex-A activity.
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GAUCHER DISORDER
It is genetically inherited autosomal recessive storage disorder, occurs due to the defiency of enzyme called glucocerebrosidase.
A fatty substance known as glucocerebroside build up to toxic levels in the spleen, liver, lungs, bone marrow, and sometimes in the brain.
3 types: type 1,type 2, type 3 It is most prevalent in the
Ashkenazi Jewish population (Jews of Eastern European ancestry).
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GAUCHER DISORDER
SYMPTOMS:
enlarged liver and spleen
fatigue due to anemia
low blood platelets
bone pain
bone deterioration and weakening (osteoporosis)
lack of coordination (ataxia)
brain damage, seizures
DIAGNOSIS:
Enzyme assay for measuring glucocerebrosidase (GC) activity.
Genetic testing
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NEIMANN-PICK DISORDER
This disease refers to a group of autosomal recessive inherited disorders known as leukodystrophies or lipid storage disorders in which certain fats accumulate in the tissues like the brain and liver and cause damage due to the defiency of Acid Sphingomyelinase (ASM).
The four types of Niemann-Pick disease are commonly called Type A, Type B, Type C and Type D.
Sometimes Type A and B are grouped together as Type I and C and D are grouped together as Type II.
Certain group of population have high risk like:
Ashkenazi Jewish population (Types A and B)
French Canadian population of Nova Scotia (Type D)
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NEIMANN-PICK DISORDER
SYMPTOMS: enlarged liver brain damage difficulty walking and swallowing increased sensitivity to touch difficulty speaking loss of muscle tone (hypotonia) learning difficulties
DIAGNOSIS: measuring the ASM activity in white blood cells. examining a skin sample (biopsy) for cholesterol
storage.
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POMPE DISEASE
Caused due to the lack of an enzyme called acid alpha-1,4-glucosidase (also called acid maltase), thus called as glycogen storage disease or acid maltase deficiency.
Leads to glycogen builds up in the body's cells and causes damage, mainly to muscles.
2 forms: Infantile form, Late-onset form.
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POMPE DISEASE
SYMPTOMS:
enlarged and weak heart
muscle weakness
respiratory difficulties
DIAGNOSIS:
Usually confused with multiple sclerosis.
Enzyme assay for measuring acid alpha-glucosidase activity.
in adults, a blood test can be used.
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TREATMENT OF LSD'S
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ENZYME REPLACEMENT THERAPY FOR LSD'S
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REFERENCES
Molecular biology of the cell, 5th edition Bruce Alberts et. al.
Cell and molecular biology, 6th edition Karp
Molecular cell biology, 5th edition Lodish et.al.
Membrane dynamics and the biogenesis of lysosomes (Review) J. Paul Luzio, Viviane Poupon, Margaret R. Lindsay, Barbara M. Mullock, Robert C. Piper and Paul R. Pryor.
Lysosome:- death by cell malfunction Danton H o'Neal.
Lysosomes and mitochondria in the commitment to apoptosis: a potential role for cathepsin D and AIF. M Jattela, C Cande´, G Kroemer
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REFERENCES
http://www.merckmanuals.com/professional/pediatrics/inherited_disorders_of_metabolism/lysosomal_storage_disorders.html
http://emedicine.medscape.com/article/1182830-overview
http://www.nature.com/nrm/journal/v5/n7/fig_tab/nrm1423_F4.html
http://igitur-archive.library.uu.nl/chem/2006-1201-210615/2.Futerman2004%20pp554-65.pdf
http://www.lsdss.org
http://www.bmrn.com/patients-physicians/mps-i.php
http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=801
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THANK YOU...