12

Question 1

What is proteostasis

Answer 1

Maintenance of the functional proteome

Question 2

What are two major responses to maintain proteostasis

Answer 2

Unfolded protein response

Heat-shock response

Question 3

What is UPR

Answer 3

Secretory pathway proteostasis:

• Triggered by accumulation of unfolded/misfolded proteins in ER
• Resulting in chaperone production
• Unsuccessful folding causes cleavage by proteasome and apoptosis

Question 4

What is HSR

Answer 4

Cytoplasmic proteostasis:
- Well-ordered transcriptional upregulation of many chaperones in response to stress including thermal, environmental infections and other conditions

Question 5

What are two treatments to maintain proteostasis

Answer 5

1: Pharmacgological chaperone
2: Proteostasis regulator

Question 6

What is a pharmacological chaperone

Answer 6

Small molecule that stabilises folded, functional form of mutant protein

Question 7

What is a proteostasis regulator

Answer 7

Small molecule that ffects chaperones via UPR or HSR or targeting for degradation

Question 8

What is the normal function of transthyretin

Answer 8

Storage and transport of hormone thyroxine and transport of retinol in a complex with retinol binding protein (RBP)

Question 9

What are some TTR amyloid diseases

Answer 9

Senile systemic amyloidosis (SSA)

Familial amyloidotic polyneuropathy (FAP)

Question 10

What occurs in TTR amyloid diseases (2)

Answer 10

Deposition of fibrils in nerves causing limb weakness and sensory loss
Liver, spleen, heart and vitreous humour can also be affected

Question 11

What leads to amyloid formation with TTR

Answer 11

Instability of TTR tetramer
Tetramer dissociation at acidic pH - lysosomes
Monomer is amyloidogenic form

Question 12

What is a small molecule pharmacological chaperone used for amyloid misfolding disorder

Answer 12

Tafamadis (Vyndaqel)

Question 13

What is Gaucher disease

Answer 13

Lysosomal storage disorder caused by mutations in the GBA gene which encodes glycocerebrosidase

Question 14

What does Gcase do

Answer 14

Degradatation of glucocerebroside - cell wall

Question 15

What results from deficiency in GCase activity (5)

Answer 15

1) Skeletal abnormalities
2) Liver and
3) Spleen enlargement
4) Anaemia
5) Cognitive deterioration

Question 16

What occurs in Gaucher disease to GCase (2)

Answer 16

GBA mutations affect GCase folding- extensive ER-associated degradation (ERAD)
Loss of function due to increased degradation of GCase - lack of correct trafficking to lysosome

Question 17

What are some Gaucher disease treatment options

Answer 17

Imiglucerase (Cerazyme) and velaglucerase replacement enzyme therapies

Question 18

What forms transient complexes with chaperones to facilitate folding

Answer 18

Nascent polypeptides

Question 19

How do NN-DNJ and MG-132 work together

Answer 19

NN-DNJ is a pharmacological chaperone that binds to enzyme and stabilises it
MG-132 is a potent proteasome inhibitor - stops degradation of unfolded protein

Question 20

What causes CF

Answer 20

Mutations in the Cystic Fibrosis Transmembrane Regulator gene

Question 21

What does CFTR encode + mutation cause

Answer 21

cAMP-regulated chloride channel = defective chloride secretion

Question 22

What happens in airways of CF sufferers

Answer 22

1) Impaired mucociliary clearance
2) Recurrent bacterial infections
3) Severe lung damage

Question 23

What are the two effects of the most common mutation F508

Answer 23

1) Decreased trafficking from ER to plasma membrane leading to increased degradation by QC mechanisms
2) Channel gating defect - opens 1/3 of WT

Question 24

What is another channel function mutant in CF

Answer 24

G551D

Question 25

What occurs in normal trafficking of CFTR to the cell membrane (3)

Answer 25

1) Nascent CFTR chain into ER for N-glycosylation and folding with chaperone calnexin
2) Export to Golgi for complex glycosylation
3) Insertion in plasma membrane

Question 26

What occurs in trafficking defect F508

Answer 26

1) Misfolded protein detected in ER
2) Mutant protein removed from ER
3) Degraded by ubiquitin/proteasome system (ERAD
4) May trigger unfolded protein response

Question 27

What occurs in functional defect G551D and F508 (2)

Answer 27

1) Trafficked to surface but not 100% correctly folded

2) Gating defects

Question 28

What are two approaches for pharmacological treatment of CFTR

Answer 28

1) Activation of CFTR channel at membrane

2) Correction of traffickign defect

Question 29

What drug corrects function defect of CFTR

Answer 29

Vertex VX770 (Kalydeco) but only for G551D

Question 30

What drug is being tested for trafficking defect

Answer 30

Vertex VX-809 clinical trials

Question 31

What disease do people with Gaucher disease have a risk of developing?

Answer 31

Parkinson’s disease

Question 32

What are some suggestions as to how Gaucher disease causes Parkinson’s disease (2)

Answer 32

1) Dysfunction of lysosomes lead to accumulation of a-synuclein aggregates
2) Cell stress and activation of UPR leading to ERAD of both substrates