Prions Flashcards
What are prion diseases called?
Transmissible spongiform encephalopathies
What is the pathology caused by prion diseases?
- neural death
- vacuolization
- proliferation of astrocytes
What was the first prion disease discovered?
Scrapie in sheep
What observations were made with the agent causing scrapie?
- agent is very stable to heat and irridation
- long incubation period
- can be (very ineffectively) transmitted to mice
- mouse adopted strain can be efficiently transmitted to mice
What was a major breakthrough in prion research and what new observations were made of the infectious agent causing scrapie?
Breakthrough = scrapie produces disease in hamsters in only 2 months
Observation:
- infectious agent lacks nucleic acid
- consists of a single protein
What is the prion protein called?
Prp
Describe the properties of the protein PrP (normal fucntions)
- not essential for viability of mice
- cell-surface GPI-anchored memb protein that binds Cu2+
- plays a role in myelination of peripheral neurons, and regulation of cell growth, differentiation and signaling pathways
What are some simililarites and differences noted between PrP of the infectious agent and normal PrP?
similarity:
- has exact same a.a sequence
difference:
- folded to aberrant shape
- resistant to proteases
- forms large aggregates -> aggregates kill neurons
What are the structural differences between PrPc and prion?
PrPc = lots of alpha helices
prion = less alpha helices and lots of beta barrels
Why is PrPsc (scrapie) infectious?
can convert molecules of PrPc to the misfolded PrPsc state (irreversible)
Where does PrPsc come from?
- spontaneous misfolding of PrPc (very rare)
- genetic mutations that increase the likelihood of PrPc -> PrPsc (e.g. fCJD and FFI)
- infection
What is the dominance of mutations that create amino acid changes in PrPc?
autosomal dominant
Describe the evidence for the protein-only hypothesis
- brain lesions in TSE of all species contain misfolded protease-resistant PrP
- knockout mice lacking the PrP gene are immune to prion disease
- mice containing heterologous PrP genes display a modified species barrier
- Protein Misfolding Cyclic Amplification (PMCA)
Describe how the species barrier was modified with scrapie
Hamster can efficiently infect hamsters and mice containing the hamster PrP gene (inefficiently infects WT mice)
- infected mice with the hamster PrP gene efficiently infected hamsters but inefficiently infected WT mcice
Mouse can efficiently infect WT mice, but not hamsters or mice with the hamster PrP gene
Describe how PMCA works
PrPc + PrPsc (seed material) -> converts to PrPsc aggregate -> sonification breaks the aggregate -> small aggregates -> repeat conversion and sonification steps many times -> amplified PrPsc
How does protease treatment detect prions?
- normal protein -> cleaved into many small pieces
- prion -> cleaved into few large pieces
What characterizes the different scrapie strains in sheep?
different lag times and symptoms
What are the different prion strains in humans, what’s a similarity between the strains, and what kind of inheritance do prions show?
strains = CJD, vCJD, FFI
all caused by the same misfolded PrP
inheritance = protein-based
What are the routes of infection for prions? Name an example for each route
- ingestion of infected body parts
- BSE and Kuru - contaminated surgical instruments (can’t sterilize by autoclaving)
- CJD - unknown
- scrapie (primarily mother to offspring, not clear how)
Describe some characterisitics of Kuru (e.g. where, symptoms, mode of spread, etc)
- affected inhabitants in the highlands of New Guinea
- symptoms included difficuslt in coordinating movements
- death resulted in < 1 year
- spread through ritual cannibalism at funerals
- age and gender bias
- disease how now been eliminated
What are the three different routes that CJD occurs through
- sporadic CJD (sCJD)
- familial/inherited (fCJD)
- iatrogenic/acquired (iCJD)
Describe sCJD
- occurs spontaneously
- very rare
- onset = 65yr
- memory and mental acuity loss
- fatal after 3 months
Describe fCJD
- 10% of cases
- onset = 27 years
- mut in PrP gene that increases the pbty of prion formation
Describe iCJD
transmission from infected person to uninfected
- contaminated surgical instruments
- contaiminated extracts of pituitary glands (pooled human growth hormone and this infected 50 people)
