Lecture 16 - Prion Disease Flashcards
What is a prion?
A misfolded protein that can induce abnormal folding of normal variants of the same protein and trigger cellular death.
Prion protein can act as a gene.
What are the known prion diseases in man?
Kuru (infectious)
Creutzfeld-Jacob disease (sporadic, inherited, infectious)
Fatal familial insomnia (inherited)
Gertsmann-Sträussler-Scheinker (inherited)
What are some prion diseases known in animals?
Scrapies - found in sheep and was the first clue prion diseases were being transmitted by a protein.
Bovine/feline/mink spongiform encephalopathy/CWD.
Describe Kuru.
Fatal neurological disease.
Passed through cannibalistic practices and eating the brain of infected individuals.
Long incubation period - death within 2 years of presentation.
Describe CJD.
100-150 patients die each year in UK of CJD.
80% of all human TSEs.
Can be inherited or infectious.
Iatrogenic - passed by humans in some way (doctors in this case).
Rapidly progressing myoclonus, ataxia and dementia.
Spongiform changes (holes in the brain due to cell death), neuronal loss and gliosis all present.
How do prions get from the digestive system to the brain?
Peyer’s patches connect the gut to the peripheral nerves and lymphatic system.
Infectious proteins transmitted up through this lymphatic system and into the peripheral nerves to the brain where they cause damage.
What is the prion (protein only) hypothesis?
Prion diseases are caused by a protein that has adopted an abnormal form in the absence of a nucleic acid by transmission of its altered folding to the normal host version of the protein.
How was the prion hypothesis discovered?
Infectious particle does not have DNA - particle isolated and treated with UV light which would normally break up nucleic acids. On all treatments this did not affect transmission and there was no viral or immune response.
Proteinaceous infective particle set up - prion protein being one of two type a natural form and an infectious form.
Describe the natural prion form.
PrPc.
Highly conserved cell surface protein.
Expressed in many tissues but high levels in neurons and glial cells.
Physiological function is unknown.
Experiment - identified the prion encoding gene in mice and knocked out to see what happens to the mouse > appeared normal.
Describe the infectious prion form.
PrPsc.
Found as aggregated particles in the brain of affected individuals.
Insoluble particles that are resistant to proteases.
Secondary structure that is mostly beta sheets.
What is the similarities and differences between PrPc and PrPsc?
Have the same primary sequence.
Difference is when they fold into the secondary structure they become very different.
PrPc = alpha helices
PrPsc = mainly beta sheets.
How does an infectious particle replicate?
Mainly beta sheets finds another molecule of the prion protein and binds to it and makes it somehow change structure from alpha helices to beta sheets.
This causes aggregation of particles.
Mutations in what gene cause prion disease?
Prnp1
Encodes the prion protein and is highly polymorphic.
How can we test the infectious prion hypothesis?
When you knock out the gene that encodes the normal physiological function in PrPc, the mice are perfectly normal.
Infectious bolus of the prion injected into normal mouse and it dies.
If you inject the infectious particle into the mouse that does not express the normal prion protein, there is no deathbecause the infectious particle does not have anything to template/aggregate with.
How can prions be resistant to proteases?
There are different strains - all have the same primary sequence but secondary sequence differs.
