Lecture 8: Diseases Flashcards
What are the three diseases focused on?
Chylomicron retention diseases
Familial hypercholesterolaemia
Lysosomal storage diseases
How are chylomicrons synthesised?
- PreChylomicrons assemble in ER
- Packaged into transport vesicles for delivery to golgi
- Mature into chylomicrons in golgi
- Released by exocytosis and enter capillaries
How is the synthesis of chylomicrons defective and cause disease?
- COPII coat that does cargo export from ER doesn’t assemble
- Prechylomicrons are trapped in the ER and can’t move to the golgi
How does Sar1 cause the formation of COPII vesicles?
- Sar1p in the cytosol is off and bound to GDP
- Regulatory protein on ER membrane activates Sar1p into Sar1-GTP
- Initiates assembly of COPII coat proteins
What are the two types of Sar1 genes in humans?
Sar1a
Sar1b
How do mutations in Sar1b cause chylomicron retention disease?
- Sar1b promotes export of prechylomicrons
- Mutations in Sar1b stop Sar1b from being made and makes the GTP binding site defective
- This prevents preChylomicron export from the ER
Why does mutation of Sar1b only affect export of preChylomicron?
Sar1a is active
Sar1a does transport of most other cargo
Sar1b are only for specific cargo
What are the symptoms of chylomicron retention disease?
Impaired absorption of fats and cholesterol
Slow growth
Wait gain
Affects gastrointestinal nervous system
What is a treatment for chylomicron retention disease?
Low fat diet
Minimise accumulation of preChylomicrons
What does familial hypercholesterolaemia cause?
Defects in cholesterol uptake
Cholesterol accumulates in blood causing atherosclerosis
What are the 4/6 different classes of mutation that effect the LDL receptor and cause familial hypercholesterolaemia?
Class 2
Class 4
Mutations in cargo adaptors
Class 3
What is the class 2 mutation that causes familial hypercholesterolaemia?
LDL receptor proteins are misfolded
Retained by ER quality control
What is the class 4 mutation that causes familial hypercholesterolaemia?
- Clustering of receptor into coated pits and internalisation of receptor doesn’t happen
- Mutations in cytoplasmic tail of LDL receptor stop the adaptor protein from binding
- LDL receptor isn’t recruited to clathrin coated vesicles
- Binds as normal but not internalised
How do mutations in cargo adaptors cause familial hypercholesterolaemia?
Mutations in gene for LDLRAP1 cause loss of the protein
Causes autosomal recessive hypercholesterolaemia
What are class 3 mutations that cause familial hypercholesterolaemia
Normal synthesis and abnormal binding
What are two overall treatments for familial hypercholesterolaemia?
Inhibit cholesterol synthesis
Inhibit dietary cholesterol absorption
What is the method of inhibiting cholesterol synthesis to treat familial hypercholesterolaemia?
Stimulates LDL receptor expression
Increased LDL uptake Good for heterozygotes
What is the method of inhibiting dietary cholesterol absorption to treat familial hypercholesterolaemia?
Ezetimibe acts in intestine
What is the cause of lysosomal storage diseases?
Defects in acid hydrolases and transporters
What are two examples of lysosomal storage diseases?
Niemann-pick disease
Gaucher disease
What is the cause of gaucher disease?
- Mutations cause misfolding of lysosomal acid B-glucosidase
- Retention in ER
- Absence causes accumulation of glucosylceramide
What are three potential treatments for lysosomal storage diseases/gaucher disease?
Enzyme replacement therapy
Substrate reduction therapy
Pharmacological chaperones
What is the treatment of enzyme replacement therapy for lysosomal storage diseases?
Inject synthetic enzymes to be taken up by endocytosis
What is substrate reduction therapy to treat lysosomal storage diseases?
Reduce amount of glycosylceramide in lysosomes
EG miglustat
What are pharmacological chaperones to treat lysosomal storage diseases?
Drugs promoting correct folding
Increase amount of enzyme that escapes ER quality control and reaches the lysosome
