Protein Misfolding and Disease Flashcards
What percentage of synthesized polypeptide chains are misfolded during or after synthesis?
As many as 50%
What factors contribute to increased protein misfolding?
Over-production Impaired degradation Mutations Heat Shock Absence of binding partners Alterations in post-translational processing Oxidative stress Aging
What are the two possible outcomes of a misfolded protein?
Gain of function: toxicity
Loss of function: loss of biological function
What are amyloid fibrils?
Accumulations of misfolded proteins into beta sheets (perpendicular beta strands to the fiber axis)
Dyed with congo red or thioflavin
What disease is characterized by amyloid plaques?
Alzheimers
Are amyloids always pathogenic?
Nope
How are misfolded proteins dealt with in the cytoplasm?
JUNQ (degradation -> eventually goes to proteasome)
OR
IPOD (aggregation)
What determines whether misfolded proteins go to JUNQ or IPOD?
Ubiquitination status…
Ubiquitinated proteins go to JUNQ for degradation
IPOD proteins just get sequestered away and sit there
What are some major diseases of protein misfolding?
Alzheimer's Huntingtons Parkinsons ALS Tauopathy
What plaques form in Alzheimer’s
Extracellular amyloid plaques/Abeta plaques which is made from amyloid precursor protein (APP)
Neurofibrillary tangles (Tau)
What protein deposits form in Parkinson’s
Lewy bodies outside neurons
Do prion proteins have DNA or RNA?
NO!
What is characteristic of CJD?
Spongiform encephalopathy/vacuolation of the grey matter of the brain
What are human prion diseases?
Creutzfeldt-Jakob Disease (CJD)
Kuru
Gerstmann0Straussler Syndrome (GSS)
Fetal Familial Insomnia (FFI)
What are clinical features of prion diseases?
Dementia
Ataxia
Tremor
Myoclonus (involuntary muscle jerks)
What is the incubation period of prion diseases?
Years
What are infectious prion diseases?
Kuru, BSE, vCJD, CWD
What are genetic prion diseases?
CJD, GSS, FFI
100% penetrance
Can CJD also be sporadic?
Yes
What are the two forms of prions? How are they the same/different?
PrPC = non-infectious
PrPSc = infectious
Same AA sequence but different folding!
Describe PrPc
Normal cell-surface protein
Non-infectious
Monomeric
ALPHA HELIX
Describe PrPSc
Infectious
Diseases
Aggregated
BETA SHEET
What percentage of Alzheimer’s cases are inherited?
10% 3 known genes
