Prion vignette Flashcards
presentation of prion disease
rapidly progressive dementia (AD not rapid)
MRI suggestions of prion dz dx
brightness of thalamus
extra fluid
hyperintensity of gray matter (T2, DWI)
autopsy results prion dz
shrunken brain
histology shows loss of neurons, vacuolizaiont of the neuropil, and proliferation of radtive astrocytes
Immunohistochemistry using antibody for prion protein positive
timeline of prion dz
scrapie (1700s)
Kuru - New Guinea (1950s) ritual cannibalism
Molecular Biology (1980s)
BSE & CWD (1990s)
Bovine Spongiform Encephalopathy (BSE)
post-mortem chemical stain
vacuoles, bubble-like “holes” almost always specific to dz, decreased neurons
Chronic Wasting Disease (CWD)
epidemic centered around Fort Collins, CO
has attack rates approaching 100% in deer, lower in other species
prion dz of humans
infections in <1% (dietary or latrogenic)
genetic in 10%
sporadic in 90% (unknown cause)
Discovery of the prion
Stanley Prusiner developed assay for prion extraction Infectious fraction of brains from hamsters with scrapie - Detergent extraction - PEG precipitation - Proteinase K digestion - Nuclease digestion - Sucrose gradient ---contained only a protein---
genetic code for prion protein
human prion protein on chromosome 20, unknown function
infectious prion is an alternative form of a host protein
healthy and unhealthy animals express the protein
PrP^c
Prion Protein Cellular (normal)
PrP^sc
scrapie prion protein (diseased)
difference between PrP^c and PrP^sc
abnormal form has: large increase in beta-sheets not soluble in mild detergents resists protease no difference in covalent structure
protease inhibition of PrP^sc
resistant core of beta-sheets blocks protease
goes from 35kD to ~30kD
prion protein propagation model
exogenous aggregates of malformed protein “recruits” normal protein to change shape
may dislodge a chaperone to facilitate this process, creating a propagation sequence
inheritance of familiar prion disease
autosomal dominant
denatured malformed prion refolding
attains normal structure, b/c aa sequence is same as normal protein
prion strains
distinct isolates with characteristic features such as incubation time in defined host, clinical signs, distribution of sx leading to death among different “strains” of prion disease
what is prion dz
normal aa sequence protein, coded from genome, misfolded into malignant form
BSE v CJD
actually different strains, show up differently on gel
annual incidence of neurodegenerative dz
AD 450,000 PD 50,000 ALS 5000 FTLD 2500 PSP 2000 MSA 1400 Prion 300
financial cost of dementia
~1% of world GDP
similarity of prion dz to AD
beta-amyloid can act like a malformed prion, but AD never shown to be infectious
