Prion Vignette Flashcards
Prion disease can be acquired in one of three ways
infectious
genetic
sporadic
Infectiously acquired prion disease -1%
could be dietary (vCJD/kuru)
could be iatrogenic (pituitary hormones / dura mater)
Genetically acquired prion disease (3) 10%
*has to do with gene coding for prion protein
familial CJD
Gerstmann-Strausser syndrome (GSS)
Fatal familial insomnia (FFI)
Sporadic - 90%
Creutzfeldt Jakob disease (CJD)
What is the infectious agent in prion disease
A protein
“The prion protein”
Where does the prion protein come from?
Amazingly, the prion protein is the product of a normal chromosomal gene (PRNP) that is found in all mammals (conserved)
BUT IF the prion protein is a product of a normal gene, what’s the problemo?
Well, the infectious prion is an alternative form of the host protein - it folds up differently
How is PRPc different from PRPsc
PrPsc is protease resistant - if you add protease to PrPc, it dissolves completely
- if you add protease to PrPsc, it only partially is digested
What explains why PrPsc is only partially digested by proteases, while PrPc is fully digested?
PrPsc is comprised of a significant number of beta sheets, while PrPc is mainly alpha helix
IMPORTANT!
So, we know PrPsc is causing a problemo…we know that it is found in prion disease and not in healthy animals, and we know that it isn’t soluble in mild detergent while normal PrPc is… thus, wouldn’t you think that they have differences in their covalent structure?
NO!!!!!!!
THE COVALENT STRUCTURE OF THE PrPc and PrPsc are IDENTICAL!!!
CRAZY!
Recall… covalent is the primary aa sequence AND the glycosylation!
(exception is genetic cases)
What is the secondary of PrPc vs PrPsc
PrPc - alpha helix w/ unstructured N terminus
PrPsc - 40% beta sheet
What is the tertiary structure of PrPc vs PrPsc
PrPc - globular
PrPsc - unknown b/c insoluble
What is the quarternary structure of PrPc vs PrPsc
PrPc - mono or oligomeric
PrPsc - bsheet linked aggregates
What is the significance of the difference in PrPc vs. PrPsc quaternary structure in terms of protease degradation
The PrPc mono or oligomeric nature allows easy access by protease to digest
The PrPsc beta sheet aggregates inhibit access of the protease to the PrPsc core and thus remains undigested (Core)
Current model of infectious prion propagation
Exogenous infectious prion protein PrPsc arrives –>
Interacts with normal PrPc –>
Causes normal PrPc to attain PrPsc confirmation –>
Splits apart after a while–>
Now two PrPsc aggregates –> cycle continues
Current model of sporadic propagation
Spontaneous conversion of PrPc to PrPsc aggregates –> induce normal PrPc to adopt PrPsc confirmation –> cycle continue
If we denature prion PrPsc and allow it to refold, what should it refold as?
PrPc
Because it is the same covalently
What are prion strains?
Distinct isolates with characteristic features, such as incubation time in defined host, clinical signs, distribution of protease resistant PrP in brain of affected animal. These features are stable on serial propagation. Certain biochemical properties of PrP are strain specific
The fact that Hyper prion has a clinical course of 70 days and Drowsy has a clinical course of 148 illustrates what?
Prion strains have propagatable characteristics … including incubation time
What 4 characteristics are unique to prion strains
incubation time
symptoms
distribution of histological lesions
distribution of PrPsc in brain
Do different prion strains have different PrP protease resistant fragment sizes?
Yes… and they are propagable to mice from humans
Are Bovine Spongiform encephalopathy and variant CJC the same?
Linked?
What is BSE/vCJD?
A unique strain of prion
Is BSC/vCJD different than sporadic?
Yes… smaller protease fragment
