Lecture 8: Diseases

Question 1

What are the three diseases focused on?

Answer 1

Chylomicron retention diseases
Familial hypercholesterolaemia
Lysosomal storage diseases

Question 2

How are chylomicrons synthesised?

Answer 2

1. PreChylomicrons assemble in ER
2. Packaged into transport vesicles for delivery to golgi
3. Mature into chylomicrons in golgi
4. Released by exocytosis and enter capillaries

Question 3

How is the synthesis of chylomicrons defective and cause disease?

Answer 3

1. COPII coat that does cargo export from ER doesn’t assemble
2. Prechylomicrons are trapped in the ER and can’t move to the golgi

Question 4

How does Sar1 cause the formation of COPII vesicles?

Answer 4

1. Sar1p in the cytosol is off and bound to GDP
2. Regulatory protein on ER membrane activates Sar1p into Sar1-GTP
3. Initiates assembly of COPII coat proteins

Question 5

What are the two types of Sar1 genes in humans?

Answer 5

Sar1a
Sar1b

Question 6

How do mutations in Sar1b cause chylomicron retention disease?

Answer 6

1. Sar1b promotes export of prechylomicrons
2. Mutations in Sar1b stop Sar1b from being made and makes the GTP binding site defective
3. This prevents preChylomicron export from the ER

Question 7

Why does mutation of Sar1b only affect export of preChylomicron?

Answer 7

Sar1a is active
Sar1a does transport of most other cargo
Sar1b are only for specific cargo

Question 8

What are the symptoms of chylomicron retention disease?

Answer 8

Impaired absorption of fats and cholesterol
Slow growth
Wait gain
Affects gastrointestinal nervous system

Question 9

What is a treatment for chylomicron retention disease?

Answer 9

Low fat diet
Minimise accumulation of preChylomicrons

Question 10

What does familial hypercholesterolaemia cause?

Answer 10

Defects in cholesterol uptake
Cholesterol accumulates in blood causing atherosclerosis

Question 11

What are the 4/6 different classes of mutation that effect the LDL receptor and cause familial hypercholesterolaemia?

Answer 11

Class 2
Class 4
Mutations in cargo adaptors
Class 3

Question 12

What is the class 2 mutation that causes familial hypercholesterolaemia?

Answer 12

LDL receptor proteins are misfolded
Retained by ER quality control

Question 13

What is the class 4 mutation that causes familial hypercholesterolaemia?

Answer 13

• 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

Question 14

How do mutations in cargo adaptors cause familial hypercholesterolaemia?

Answer 14

Mutations in gene for LDLRAP1 cause loss of the protein
Causes autosomal recessive hypercholesterolaemia

Question 15

What are class 3 mutations that cause familial hypercholesterolaemia

Answer 15

Normal synthesis and abnormal binding

Question 16

What are two overall treatments for familial hypercholesterolaemia?

Answer 16

Inhibit cholesterol synthesis
Inhibit dietary cholesterol absorption

Question 17

What is the method of inhibiting cholesterol synthesis to treat familial hypercholesterolaemia?

Answer 17

Stimulates LDL receptor expression
Increased LDL uptake Good for heterozygotes

Question 18

What is the method of inhibiting dietary cholesterol absorption to treat familial hypercholesterolaemia?

Answer 18

Ezetimibe acts in intestine

Question 19

What is the cause of lysosomal storage diseases?

Answer 19

Defects in acid hydrolases and transporters

Question 20

What are two examples of lysosomal storage diseases?

Answer 20

Niemann-pick disease
Gaucher disease

Question 21

What is the cause of gaucher disease?

Answer 21

1. Mutations cause misfolding of lysosomal acid B-glucosidase
2. Retention in ER
3. Absence causes accumulation of glucosylceramide

Question 22

What are three potential treatments for lysosomal storage diseases/gaucher disease?

Answer 22

Enzyme replacement therapy
Substrate reduction therapy
Pharmacological chaperones

Question 23

What is the treatment of enzyme replacement therapy for lysosomal storage diseases?

Answer 23

Inject synthetic enzymes to be taken up by endocytosis

Question 24

What is substrate reduction therapy to treat lysosomal storage diseases?

Answer 24

Reduce amount of glycosylceramide in lysosomes
EG miglustat

Question 25

What are pharmacological chaperones to treat lysosomal storage diseases?

Answer 25

Drugs promoting correct folding
Increase amount of enzyme that escapes ER quality control and reaches the lysosome