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 different routes in which TSEs can be acquired?
Give an example of the TSEs that could be caused due to each one?
dietary consumption of infectious prion protein – KURU, nvCJD, BSE
“iatrogenic- relating to illness caused by medical examination or treatment” infection with infectious prion protein – CJD, scrapie
mutations in prion protein making it “infectious” – genetic CJD, FFI
spontaneous conversion of normal prion protein into “infectious” prion protein- sporadic CJD
What are the common clinical features of TSEs?
locomotor abnormalities – shaking, tremor, unsteady gait, muscle jerks
speech abnormalities as circuits where aggregations are occurring could be involved in speech and therefore causes negative affects
psychiatric abnormalities – inappropriate laughter, depression
rapid and progressive dementia
sleep disturbances
What are the common neuropathological features of TSEs?
The cell death which causes ‘holes’ makes it look spongy
Amyloidosis is due to aggregation
Why are animal models commonly used to study TSEs?
Purer form of disease
Play around with genetics to test hypothesis e.g., via KO
Shorter period to model diseases as they have a shorter life span
Modelling as aspect of the disease (the animal does not have AD for example they just have a recreation of one aspect of the disease. Its only in prions and HD do we say we model the disease. This is because these diseases are genetic and everything down stream of this abnormality will happen).
What advantages are there with modelling PrPsc?
“Model systems are usually designed to recapitulate only specific aspects of the disease, such as a pathological phenotype, a pathomechanism, or to test a hypothesis”.
PrPsc infection is all that is needed to recreate disease in animals
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
What are the main genes that are involved in the pathogenic mechanism of TSEs?
Involves conversion of PrPc to PrPsc (PrPsc is not toxic without the PrPc substrate template conversion, toxicity is not from loss of function of PrPc)
- mice devoid of PrPc do not get infected by PrPsc
- re-introduction of PrPc gene makes mice susceptible to disease again
What is PrPc?
PrPc is a synaptic protein involved in synaptic transmission, the role is still unknown, but if it is removed the animal doesnt die which suggests there is something else being upregulated
- The more PrPsc there is, the worse the effects are
What experiments can be done to test the hypothesis of the role of PrPsc?
The more PrPsc there is, the worse the effects are
Experiments to do to test hypothesis? - sort of things to say and question in exams
Experiments: test synaptic transmission, signal transduction (via electrode) at NMJ, control= no prion, experimental= presence of prion (inject PrPsc or feed it the meat i.e., the diseased brain)
The conversion of normal prion is important for what?
Pathogenesis
Compare the differences between PrPc and PrPsc
Why is PrPsc resistant to denaturing?
Misfolded proteins get beta sheet conformations; having beta sheet makes it more stable due to presence of more hydrogen bonds between amino acid side chains. This makes it stable and harder to denature and convert (hence why PrPsc is resistant to denaturing)
Misfolded shape not detected by proteases
Once PrPc is converted to PrPsc, how does neurodegeneration occur?
- Loss of normal functon of PrPc
Function will be missed over time but may not be noticed straight away as body will not use energy making a protein which isnt valuable
KO models have adapted to not having that protein as protein has been KO from the start, so must take the results gained from these models with a pinch of saly
What else is being upregulated to counteract that proteins that been KO in the models?
- Toxic gain of function of PrPsc
PrPsc is unlikely to be toxic by itself because it needs PrPc to cause disease
- Activation of inflammatory response by PrPsc
Tell me the different pathogenic mechanisms involved with prion disease and the areas of the neuron they are involved in
What are some therapeutic interventions of TSEs?
- Reducing conversion of Prpc to Prpsc
- Halt neurodegenerative process?
Clear aggregated protein- Turmeric enhances heat shock proteins which helps with misfolded proteins –> normal proteins and helps clear aggregated proteins
Compare AD and TSEs
Overview
At the end of this series of lectures you should be able to:
- explain why we think prion is the infective agent in TSEs
- understand that the conversion of PrPc to PrPsc underlies the pathogenic mechanism
- suggest suitable therapeutic interventions
