B2.025 Protein Aggregation Diseases Flashcards
what are 3 types of folding diseases?
amorphous deposits, amyloid fibers, native like deposits
what types of diseases were first associated with pathological protein folding?
prion disease
ex: mad cow, scrapie, kuru, Creuzfeldt-Jacob
why can individuals who spent time in the UK between 1980-1996 not donate blood?
there were cases of mad cow disease that resulted in transmissible spongiform encephalopathies in humans
what interconversion is associated with normal/abnormal prion proteins?
normal- membrane associated and lapidated
abnormal- amyloid formations
why are prion amyloids difficult to get rid of?
heat resistance, little proteolysis
how are amyloidogenic proteins similar/different?
in general, large variation between types of proteins that can form amyloids
- long strands of hydrophobic residues common
- many, but not all, have membrane interactions
is there cross seeding in amyloids?
no, proteins only form amyloids amongst the same protein
what is a formation composed of multiple proteins called?
amorphous aggregate
what 5 amyloidogenic proteins were discussed?
prion protein, APP, alpha-synuclein, huntingtin, beta-2-microglobulin
is AD amyloid a cause of consequence?
we don’t know, treatments have been targeting it as a cause, but so far haven’t been effective….maybe a protective consequence instead
how could smaller oligomers be toxic in AD?
could form pores that poke holes in membranes, compromising their structures
what types of aggregations are particular to ALS?
bunina bodies;
cystatin C and transferrin
what is significant about poly Q proteins?
series of Q repeats, the longer the poly-Q the more aggregation and more disease
what is the normal function of huntingtin?
possible scaffolding protein linked to diverse cellular pathway
what is the relationship between number of CAG repeats in Huntington’s disease and age of onset?
more CAG= more prone to aggregation = more builds up in a shorter period of time = younger age of onset
for two patients with the same number of repeats in Huntington’s, what different factors contribute to age of onset?
protein folding mechanisms differ (osmolyte level differences, chaperone protein differences)
more/less efficient clearing systems (proteasomal/lysosomal activites)
comorbidity with other aggregating proteins
modifier genes
which step(s) in the transcription/translation/expression pathway contain mechanisms of action by which mutations associated with hereditary amyloid diseases cause proteins to form aggregates?
all of them!
what is an effect of insufficient chaperone activity?
increasing number of proteins requiring degradation due to misfolding and thus an increased strain on the proteasome
why might bunina bodies form?
the components, cystatin C and transferrin could be proteostasis substrates that cannot be maintained at appropriate levels
why are many aggregation prone proteins supersaturated?
decreased solubility, more interactions with proteins that can cause aggregation just based on proximity
