B2.025 Protein Aggregation Diseases

Question 1

what are 3 types of folding diseases?

Answer 1

amorphous deposits, amyloid fibers, native like deposits

Question 2

what types of diseases were first associated with pathological protein folding?

Answer 2

prion disease

ex: mad cow, scrapie, kuru, Creuzfeldt-Jacob

Question 3

why can individuals who spent time in the UK between 1980-1996 not donate blood?

Answer 3

there were cases of mad cow disease that resulted in transmissible spongiform encephalopathies in humans

Question 4

what interconversion is associated with normal/abnormal prion proteins?

Answer 4

normal- membrane associated and lapidated

abnormal- amyloid formations

Question 5

why are prion amyloids difficult to get rid of?

Answer 5

heat resistance, little proteolysis

Question 6

how are amyloidogenic proteins similar/different?

Answer 6

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

Question 7

is there cross seeding in amyloids?

Answer 7

no, proteins only form amyloids amongst the same protein

Question 8

what is a formation composed of multiple proteins called?

Answer 8

amorphous aggregate

Question 9

what 5 amyloidogenic proteins were discussed?

Answer 9

prion protein, APP, alpha-synuclein, huntingtin, beta-2-microglobulin

Question 10

is AD amyloid a cause of consequence?

Answer 10

we don’t know, treatments have been targeting it as a cause, but so far haven’t been effective….maybe a protective consequence instead

Question 11

how could smaller oligomers be toxic in AD?

Answer 11

could form pores that poke holes in membranes, compromising their structures

Question 12

what types of aggregations are particular to ALS?

Answer 12

bunina bodies;

cystatin C and transferrin

Question 13

what is significant about poly Q proteins?

Answer 13

series of Q repeats, the longer the poly-Q the more aggregation and more disease

Question 14

what is the normal function of huntingtin?

Answer 14

possible scaffolding protein linked to diverse cellular pathway

Question 15

what is the relationship between number of CAG repeats in Huntington’s disease and age of onset?

Answer 15

more CAG= more prone to aggregation = more builds up in a shorter period of time = younger age of onset

Question 16

for two patients with the same number of repeats in Huntington’s, what different factors contribute to age of onset?

Answer 16

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

Question 17

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?

Answer 17

all of them!

Question 18

what is an effect of insufficient chaperone activity?

Answer 18

increasing number of proteins requiring degradation due to misfolding and thus an increased strain on the proteasome

Question 19

why might bunina bodies form?

Answer 19

the components, cystatin C and transferrin could be proteostasis substrates that cannot be maintained at appropriate levels

Question 20

why are many aggregation prone proteins supersaturated?

Answer 20

decreased solubility, more interactions with proteins that can cause aggregation just based on proximity