Lecture 10- Prions 101 Flashcards by Jennifer Petrie

What was the first known prion disease?

Scrape

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White circle in the brain are called?

Spongiform change

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Hans Gerhard Creutzfeldt and Alfons Maria Jakob coined what term?

Creutzfeldt Jakob Disease (CJD)

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What did Daniel Carleton Gajdusek study in 1957?

Went to Africa to study Kuru disease
Found that the disease primarily affected women and children
Tried to treat it but nothing happened
William Hadlow suggested doing an experiment to see if it was transmissable because it looked like scrape
It was found to be transmissible

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Griffith suggested it could be a stand alone protein as the infectious agent because?

Infectivity resist UV that degrades DNA/RNA
Infectivity resists decontamination methods that work against known microbes

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Stan Prusiner coined what term?

A prion

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What is a prion?

A small protinaceous infectious particle

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What is so unique about prion disease?

They can develop spontaneously
They can be inherited
They can be acquired
Prions are only proteins

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What are the normal prion proteins?

PrPsen
PrPc

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What does sen in PrPsen mean?

Means sensitive to protease digestion

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What happens if PrPsen is digested with protease K?

It eats up the whole thing

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What does the c in PrPc denote?

Cellular because this is a protein that is normally found on cells and its normal confirmation

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Describe some characteristics of PrPsen and PrPc

Sensitive to proteases
Soluble in detergents
In diverse tissue
Apparent cellular roles

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What are some cellular roles of PrPsen and PrPc?

Adhesion
Neuritogenisis
Resistance to oxidative stress
Metal binding
NMDAr binding
Abeta oligomers

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What does a normal PrP do?

Its a facilitator molecule to help other membrane molecules work better
Its protective in conditions of oxidative stress

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What happens if you remove a prion?

They will develop normally and look normal. But the moment you expose them under stress, they get a storke and the stroke in much larger

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What are the disease PrP?

PrPres, PrPsc, PrPCDJ, PrPBSE, PrPCWD

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What is the difference between a normal and infectious prion protein?

Same exact sequence but can only digest the beginning

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Describe some characteristics of PrPres

Resistant to proteases
Form insoluable aggregates that acumulates in the tissue
Nervous system, lymphoid tissue
Associated with infectivity

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What is the main difference in PrPsen and PrPres

The conformational shape

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What is the conformation of PrPc?

3 alpha helices (47%)
2 small anti-parallel beta strands (3%)
Proteinase K (PK) sensitive

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What accounts for the difference in bands in PrPc?

Size of band is different because of glycosylation

What is the conformation of PrPsc?

Loses alpha content
Increased beta sheets
Proteinase K resistant

On a gel, do the bands dissapear with PK digestion for PrPsc?

No the bands do not dissapear

Describe the prion life cycle

(Conversion) * Once it starts its conversion, it converts the neighbour prion protein and the next one (Spread) * Like a dominos effect * This is what leads to pathology * Need conversion process for infectivity * Damages the membrane enough it can no longer cope

What does it do to your brain?

* Spongiform change * Neuronal loss * Astrocytosis * Accumulation of PrPres (strain dependent)

What is astrocytosis?

Astrocytes when they react to invaders, a number of different insults, they become reactve and thats called astrocytosis (pink looking cells)

CJD is a ____ disease

Rare

What are the three types of CJD?

1. Sporadic sCJD (90%) 2. Genetic familial CJD (10%) 3. Acquired vCJD, Kuru, Iatrogenic (<1%)

What is sporadic CJD?

* Spontaneous * Misfolding a protein and your immune system isnt fast enough to correct it, then it becomes efficient on spreading and the disease is on its way

What are some types of genetic CJD?

* Familial CJD * GSS * FFI

Why was Kuru an acquired disease?

Because they were practicing cannabalism and were eating the brains and got infected that way

Sporadic CJD is ______

Always Fatal

What are some signs of sporadic CJD?

* Ataxia * Cortical visual symptoms * Progressive dementia * Myoclonus * Akenetic mutism

What is ataxia?

Problem with coordination and balance

What is myoclonus?

Fast twitching movement

What is akinetic mutism?

No movement and no speech

What is the average time to death after onset of symptoms for sCJD?

4 months

What is a definite diagnosis method for sCJD?

Neuropathological confirmation (need to look at the brain or isolate prion from the brain)

Where are the two types on a gel?

What characteristic do you use for typing?

* Codon 129 status * Glycoform ratio * Pattern of PK digestion will define the types * Have different phenotypes

What is the difference between a probable and a possible diagnosis?

Possible is just clinical signs with no tests. Probable is both clinical signs and tests

For a diagnosis, you need to have two of what clinical signs?

* Myoclonus * Visual disturbances or ataxia * Pyramidal or extrapyramidal features (parkinson like slowness and stiffness) * Akinetic mutism

For a diagnosis, you need to have one of what tests?

* EEG periodic discharges, 1-2 Hz * MRI restricted diffusion (white is abnormal) * Positive QuIC

Describe the process of QuIC (Quaking Induced Conversion)

* You take a normal prion protein shown in yellow and mix it with the patient sample, usually spinal fluid * In there, there are a few misfolded protein, so what happens when you put them together = you get converison * Get build up of beta sheet aggregates * Have one big aggregate * Then you break up into smaller peices by shaking it * You add more of the normal, mix and repeat * Get an amplification of a beta sheet signal * Do it in the presence of thioflavin T = fluorescence indicator

QuIC is highly ____ and ____

Specific and sensitive

What treatments are there for sporadic CJD?

Only symptomatic treatments

What are some potential future targets for prevention of sporadic CJD?

* Suppress PrPc * Block conversion * Improve clearance

The presence of PrPsc does not equal ____ and it is ____ dependent

* Infectivity * Dose

How is Iatrogenic CJD transmitted?

* Dura matter graft and growth hormones * Not transmitted sexually or vertically

Why does size and shape matter?

Because of the species barrier

What is a strain of prion disease?

Defined as prion isolates that consistently induce a specific disease phenotype, pathology and incubation period in a given host

What causes there to be different strains of prion disease?

Conformational differences

What is conformational drug resistance and strain selectivity?

Prevent conversion to one shape, prions will just adapt (if you wipe out strain A, then you let strain B rise)