Lecture 10- Prions 101 Flashcards
What was the first known prion disease?
Scrape
White circle in the brain are called?
Spongiform change
Hans Gerhard Creutzfeldt and Alfons Maria Jakob coined what term?
Creutzfeldt Jakob Disease (CJD)
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
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
Stan Prusiner coined what term?
A prion
What is a prion?
A small protinaceous infectious particle
What is so unique about prion disease?
- They can develop spontaneously
- They can be inherited
- They can be acquired
- Prions are only proteins
What are the normal prion proteins?
- PrPsen
- PrPc
What does sen in PrPsen mean?
Means sensitive to protease digestion
What happens if PrPsen is digested with protease K?
It eats up the whole thing
What does the c in PrPc denote?
Cellular because this is a protein that is normally found on cells and its normal confirmation
Describe some characteristics of PrPsen and PrPc
- Sensitive to proteases
- Soluble in detergents
- In diverse tissue
- Apparent cellular roles
What are some cellular roles of PrPsen and PrPc?
- Adhesion
- Neuritogenisis
- Resistance to oxidative stress
- Metal binding
- NMDAr binding
- Abeta oligomers
What does a normal PrP do?
- Its a facilitator molecule to help other membrane molecules work better
- Its protective in conditions of oxidative stress
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
What are the disease PrP?
PrPres, PrPsc, PrPCDJ, PrPBSE, PrPCWD
What is the difference between a normal and infectious prion protein?
Same exact sequence but can only digest the beginning
Describe some characteristics of PrPres
- Resistant to proteases
- Form insoluable aggregates that acumulates in the tissue
- Nervous system, lymphoid tissue
- Associated with infectivity
What is the main difference in PrPsen and PrPres
The conformational shape
What is the conformation of PrPc?
- 3 alpha helices (47%)
- 2 small anti-parallel beta strands (3%)
- Proteinase K (PK) sensitive
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?
- Sporadic sCJD (90%)
- Genetic familial CJD (10%)
- 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)
