Prion Flashcards
What is meant by Prion disease?
A prion is a type of protein that can trigger normal proteins in the brain to fold abnormally
It can affect both humans and animals and are sometimes spread to humans via infected meat products
What are the genes involved in prion disease?
It occurs when PrPc is converted to PrPsc
This is an abnormally folded form of the prion protein
What are the two main characteristics that cause prion disease?
- Misfolded proteins
- Conversion of other proteins (Naïve forms/ normal forms of the same protein
What is KURU disease?
This is a transmissable spongiform encephalopathy, a disease of the nervous system that causes physiological and neurological effects which ultimately leads to death
When was KURU disease first noticed and what is it associated with?
KURU was first noticed in 1954 by a foreigner in a young Fore tribe girl in Papua New ginea
The disease was found in women and children for the Fore tribe
The disease is associated with cannibalistic rituals carried out by the Fore tribe
When the tribe would eat the meat of those diseased patients i.e., the brain and therefore consume the causative agent
With Kuru disease what is the causative agent?
Familial?
Something infectious?
Virus?
Protein?
For each of these factors say yes or no and why that is the case
Familial? NO, genetic test done which confirmed not, was thought maybe due to some intermarriage
Something infections? YES- KURU brain homogenate can give chimpanzees disease (“infect” them- passed on between organisms)
Is it a virus? NO- no DNA or RNA molecular found in “infectious” agent, treat with antibiotic and antiviral?
Is it a protein? YES- mutations in prion gene can cause disease abnormal protein can “infect animals”, could look at gene expression levels to see if these levels change (this would be a good control as there should be no change as both the PrPs are the same), to prove definitively KO PrPsc gene
What hypothesis did Stanley Prusiner curate?
Stanley Prusiner formulated the “Protein-Only” hypothesis and coined the word “Prion” meaning protein only particle with infectious properties.
Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216:136–144
There are distinct prion “strains”
What does this mean and what is their common feature?
The different “strains” means there are different neuropathological disease patterns and biochemical profiles but their common feature is templated seeding= infectious
Seeding is when something is converted to look like the original form
Templated seeding is the name given to the conversion when the protein uses its own shape as a template and converts the abnormal protein to look like itself
Does PrPc misfold into just one shape?
No, PrPc misfolds into lots of different states not just one due to the different strains
Explain the difference between misfolded and mutant with the prion protien
Proteins have a normal structure (in this case talking about PrP)
When have a disease, the normal protein structure can become misfolded
When proteins are misfolded, you get a disease, like with PrP you can get prions disease, the misfolded proteins aggregate
Misfolded proteins also have prion like properties which means it can cause conversion
Normal –> misfolded protein state can be either sporadic (85%) (inherited, environment, lifestyle (Mediterranean diet reduces antioxidants, western diet reduces blood flow), unknown factors etc.; biggest one is aging) or due to a mutation (15%). The former is more common
Mutation will only cause misfolded protein to form in about 15% of cases so is not the main reason that these misfolded proteins are present
What are Transmissable Spongiform Encephalopathies also known as?
Prion diseases
Give an example of a transmissable spongiform encephalopathy (TSE)
KURU
Name some other TSEs?
Which ones are human and what ones are animals?
Other TSEs include CJD, GSS, FFI, BSE (mad cow disease) and scrapie
CJD, GSS, FFI and BSE are human forms of prion
BSE and scrapie are animal specific forms of prion
What are common features of all TSEs?
Transmissible
Infectious
Do the different prion strains have different clinical symptoms?
Yes
Because the different strains may be acting on different locations of the circuitry and therefore cause different clinical symptoms to be presented in the individual
What are the common neuropathological features of TSEs?
The cell death which causes ‘holes’ makes it look spongy
Amyloidosis is due to aggregation
Primates are a common animal model to use for looking at prion disease what are the pros and cons to this?
Non-human primates have been used for experiments (shown in red)
Pros: more relevant to humans
Cons: as like humans it can be unethical, also expensive
Due to some ethical problems with using primates, mice may be used to study prion disease. What are the pros and cons to this?
Mice then started to be used more than primates due to the ethical issues with primates (shown in green), fruit flies could also be used
Pros: Quick genetic lines, neural circuits are very well known and have been mapped well over the years so easier to find route of cause
Cons: some genetic manipulation may or may not be relevant to people but doing to ask a specific question, may not be translational to humans, rodent PrP has same pathogenic properties as PrPsc but won’t be as homologous as humans so not every aspect of pathogenic process will play out in animals
Compare the differences between PrPc and PrPsc
Tell me the different pathogenic mechanisms involved with prion disease and the areas of the neuron they are involved in
Compare AD and TSEs
