Prion Vignette

Question 1

Prion disease can be acquired in one of three ways

Answer 1

infectious
genetic
sporadic

Question 2

Infectiously acquired prion disease -1%

Answer 2

could be dietary (vCJD/kuru)

could be iatrogenic (pituitary hormones / dura mater)

Question 3

Genetically acquired prion disease (3) 10%

*has to do with gene coding for prion protein

Answer 3

familial CJD
Gerstmann-Strausser syndrome (GSS)
Fatal familial insomnia (FFI)

Question 4

Sporadic - 90%

Answer 4

Creutzfeldt Jakob disease (CJD)

Question 5

What is the infectious agent in prion disease

Answer 5

A protein

“The prion protein”

Question 6

Where does the prion protein come from?

Answer 6

Amazingly, the prion protein is the product of a normal chromosomal gene (PRNP) that is found in all mammals (conserved)

Question 7

BUT IF the prion protein is a product of a normal gene, what’s the problemo?

Answer 7

Well, the infectious prion is an alternative form of the host protein - it folds up differently

Question 8

How is PRPc different from PRPsc

Answer 8

PrPsc is protease resistant - if you add protease to PrPc, it dissolves completely
- if you add protease to PrPsc, it only partially is digested

Question 9

What explains why PrPsc is only partially digested by proteases, while PrPc is fully digested?

Answer 9

PrPsc is comprised of a significant number of beta sheets, while PrPc is mainly alpha helix

Question 10

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?

Answer 10

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)

Question 11

What is the secondary of PrPc vs PrPsc

Answer 11

PrPc - alpha helix w/ unstructured N terminus

PrPsc - 40% beta sheet

Question 12

What is the tertiary structure of PrPc vs PrPsc

Answer 12

PrPc - globular

PrPsc - unknown b/c insoluble

Question 13

What is the quarternary structure of PrPc vs PrPsc

Answer 13

PrPc - mono or oligomeric

PrPsc - bsheet linked aggregates

Question 14

What is the significance of the difference in PrPc vs. PrPsc quaternary structure in terms of protease degradation

Answer 14

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)

Question 15

Current model of infectious prion propagation

Answer 15

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

Question 16

Current model of sporadic propagation

Answer 16

Spontaneous conversion of PrPc to PrPsc aggregates –> induce normal PrPc to adopt PrPsc confirmation –> cycle continue

Question 17

If we denature prion PrPsc and allow it to refold, what should it refold as?

Answer 17

PrPc

Because it is the same covalently

Question 18

What are prion strains?

Answer 18

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

Question 19

The fact that Hyper prion has a clinical course of 70 days and Drowsy has a clinical course of 148 illustrates what?

Answer 19

Prion strains have propagatable characteristics … including incubation time

Question 20

What 4 characteristics are unique to prion strains

Answer 20

incubation time
symptoms
distribution of histological lesions
distribution of PrPsc in brain

Question 21

Do different prion strains have different PrP protease resistant fragment sizes?

Answer 21

Yes… and they are propagable to mice from humans

Question 22

Are Bovine Spongiform encephalopathy and variant CJC the same?

Answer 22

Linked?

Question 23

What is BSE/vCJD?

Answer 23

A unique strain of prion

Question 24

Is BSC/vCJD different than sporadic?

Answer 24

Yes… smaller protease fragment

Question 25

Characteristic plaques in variant CJD (BSE)

Answer 25

Plaques are surrounded by vaccules

Question 26

Classic sign in vCJD on mri?

Answer 26

Pulvinar sign

Question 27

What might explain different prion strains, since they are all the same protein?

Answer 27

Perhaps the folding of the protein

Question 28

How does prion disease relate to other human neurodegerative diseases at the level of protein structure?

Answer 28

In all of them, there is some protein that accumulates in an aggregated form in the brain e.g. (tau and beta amyloid in alzheimers)

Question 29

If you inocculate a mouse (mutant for beta amyloid formation) with a beta amyloid from a mouse who has already developed alzheimer’s, what happens?

Answer 29

You accelerate the progression of alz… the inocculum behaves like a prion - (and is strain specific)

Question 30

Since other neurodegenerative diseases have protein buildups like prion disease what might we ask?

Answer 30

Does a “prion-like” mechanism of autocatalytic misfolding play a role in teh progressive increase in misfolded proteins that are the hallmark of all the major neurodegenerative diseases?