12 Flashcards
What is proteostasis
Maintenance of the functional proteome
What are two major responses to maintain proteostasis
Unfolded protein response
Heat-shock response
What is UPR
Secretory pathway proteostasis:
- Triggered by accumulation of unfolded/misfolded proteins in ER
- Resulting in chaperone production
- Unsuccessful folding causes cleavage by proteasome and apoptosis
What is HSR
Cytoplasmic proteostasis:
- Well-ordered transcriptional upregulation of many chaperones in response to stress including thermal, environmental infections and other conditions
What are two treatments to maintain proteostasis
1: Pharmacgological chaperone
2: Proteostasis regulator
What is a pharmacological chaperone
Small molecule that stabilises folded, functional form of mutant protein
What is a proteostasis regulator
Small molecule that ffects chaperones via UPR or HSR or targeting for degradation
What is the normal function of transthyretin
Storage and transport of hormone thyroxine and transport of retinol in a complex with retinol binding protein (RBP)
What are some TTR amyloid diseases
Senile systemic amyloidosis (SSA)
Familial amyloidotic polyneuropathy (FAP)
What occurs in TTR amyloid diseases (2)
Deposition of fibrils in nerves causing limb weakness and sensory loss
Liver, spleen, heart and vitreous humour can also be affected
What leads to amyloid formation with TTR
Instability of TTR tetramer
Tetramer dissociation at acidic pH - lysosomes
Monomer is amyloidogenic form
What is a small molecule pharmacological chaperone used for amyloid misfolding disorder
Tafamadis (Vyndaqel)
What is Gaucher disease
Lysosomal storage disorder caused by mutations in the GBA gene which encodes glycocerebrosidase
What does Gcase do
Degradatation of glucocerebroside - cell wall
What results from deficiency in GCase activity (5)
1) Skeletal abnormalities
2) Liver and
3) Spleen enlargement
4) Anaemia
5) Cognitive deterioration
What occurs in Gaucher disease to GCase (2)
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
What are some Gaucher disease treatment options
Imiglucerase (Cerazyme) and velaglucerase replacement enzyme therapies
What forms transient complexes with chaperones to facilitate folding
Nascent polypeptides
How do NN-DNJ and MG-132 work together
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
What causes CF
Mutations in the Cystic Fibrosis Transmembrane Regulator gene
What does CFTR encode + mutation cause
cAMP-regulated chloride channel = defective chloride secretion
What happens in airways of CF sufferers
1) Impaired mucociliary clearance
2) Recurrent bacterial infections
3) Severe lung damage
What are the two effects of the most common mutation F508
1) Decreased trafficking from ER to plasma membrane leading to increased degradation by QC mechanisms
2) Channel gating defect - opens 1/3 of WT
What is another channel function mutant in CF
G551D
What occurs in normal trafficking of CFTR to the cell membrane (3)
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
What occurs in trafficking defect F508
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
What occurs in functional defect G551D and F508 (2)
1) Trafficked to surface but not 100% correctly folded
2) Gating defects
What are two approaches for pharmacological treatment of CFTR
1) Activation of CFTR channel at membrane
2) Correction of traffickign defect
What drug corrects function defect of CFTR
Vertex VX770 (Kalydeco) but only for G551D
What drug is being tested for trafficking defect
Vertex VX-809 clinical trials
What disease do people with Gaucher disease have a risk of developing?
Parkinson’s disease
What are some suggestions as to how Gaucher disease causes Parkinson’s disease (2)
1) Dysfunction of lysosomes lead to accumulation of a-synuclein aggregates
2) Cell stress and activation of UPR leading to ERAD of both substrates
