L4 Prion Flashcards
Define prion Diseases.
Prion diseases occur when proteins normally in the body misfold and cause illness. The misfolding leads to brain damage and other symptoms.
What 2 diseases does prion protein have significance in?
Cancer
Alzheimers
What does GPI do?
Facilitate attachment of prion on cell membrane
Why are the multiple bands on western blots of PrPc?
cleavages & glycosylation
Why is beta cleavage unusual?
Beta cleavage is unusual as not a traditional protease that does this - oxidative stress clips this protein off
What are genetic human prion diseases?
CJD, GSS due to PRNP mutations
What are infectious prion human diseases?
Kuru
Iatrogenic CJD
Variant CJD
Are sporadic CJD infectious?
Yes
What was Kuru associated with?
Ritualistic cannibalism
What is scrapie?
Disease of sheep
What is BSE?
Disease of cattle
What is CWD?
Disease of deer/elk
How does the prion protein change in disease?
Increase in beta sheet content & protein is resistant to proteases
not soluble in non-ionic detergents
resistant to destruction by standard decontamination processes
What are 3 forms of transmission/
Molecule-to-molecules
Host-to-host transmission
cell-to-cell transmission
How does the disease pass from cell to cell?
Use tunneling nanotubules
What mutations are found in the C & N terminus?
C = point mutations
N = insertions
What protein is AD related to?
APP
What pathway is bad processing of Ab?
Amyloidgenic pathway
beta-secretase
What pathway is good processing of Ab?
Alpha secretase
What are 3 steps to AB oligomers neuropathology?
- ab production
- assembley into oligomers
- Ab interaction with neuron receptors
What is PrPc a regulator of?
AB production
What do AB oligomers bind to?
N-terminus of membrane bound PrPc in AD brains
What does PrPc/sc expression enhance?
AB plaque production
Does PrPSc also bind to AB?
yes
What is a risk factor for AD?
V:M polymorphisms on prnp
What does X11alpha regulate?
APP processing
superoxide dismutase (regulates copper load)
What regulates X11alpha?
PrPc
What is a postive of PrP?
Binds to BACE1 - blocks AB
What happens if PrPc is turned into PrPSC?
Blocks AB production
Is binding of PRPc to AB a bad or good thing?
Bad
What strengthens neurons?
Long term potentiation
What does AB inhibit?
LTP in normal animals but not in animals lacking PrPc
What is PrPc a chaperone for?
AB toxicty
What has a higher affinity for PrPc, AB or BACE?
AB
Does PrPc reduce in an ageing brain?
Yes in the hippocampus
What is an AB receptor?
Membrane anchored PrPc
When is PrP neuroprotective?
GPI free PrP
What types of PrP inhibit AB fibrils & block neurotoxic effects of AB?
Rec full length PrP
N1 PRP23-144
What region of PrP binds to AB?
95-110
How is toxicity of AB assessed?
LDH released by neurons indicating cell leakage
What is a potential AD treatment?
PrP antibodies
What was 6D11 used for?
epitopes 93-109 - animals treated had less errors
What does AZ59 target?
epitopes 23-111 -> animals preferred to interact with novel objects
What does TW1 target?
epitopes 90 -108 –>
