Prion vignette

Question 1

presentation of prion disease

Answer 1

rapidly progressive dementia (AD not rapid)

Question 2

MRI suggestions of prion dz dx

Answer 2

brightness of thalamus
extra fluid
hyperintensity of gray matter (T2, DWI)

Question 3

autopsy results prion dz

Answer 3

shrunken brain
histology shows loss of neurons, vacuolizaiont of the neuropil, and proliferation of radtive astrocytes
Immunohistochemistry using antibody for prion protein positive

Question 4

timeline of prion dz

Answer 4

scrapie (1700s)
Kuru - New Guinea (1950s) ritual cannibalism
Molecular Biology (1980s)
BSE & CWD (1990s)

Question 5

Bovine Spongiform Encephalopathy (BSE)

post-mortem chemical stain

Answer 5

vacuoles, bubble-like “holes” almost always specific to dz, decreased neurons

Question 6

Chronic Wasting Disease (CWD)

Answer 6

epidemic centered around Fort Collins, CO

has attack rates approaching 100% in deer, lower in other species

Question 7

prion dz of humans

Answer 7

infections in <1% (dietary or latrogenic)
genetic in 10%
sporadic in 90% (unknown cause)

Question 8

Discovery of the prion

Answer 8

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---

Question 9

genetic code for prion protein

Answer 9

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

Question 10

PrP^c

Answer 10

Prion Protein Cellular (normal)

Question 11

PrP^sc

Answer 11

scrapie prion protein (diseased)

Question 12

difference between PrP^c and PrP^sc

Answer 12

abnormal form has:
large increase in beta-sheets
not soluble in mild detergents
resists protease
no difference in covalent structure

Question 13

protease inhibition of PrP^sc

Answer 13

resistant core of beta-sheets blocks protease

goes from 35kD to ~30kD

Question 14

prion protein propagation model

Answer 14

exogenous aggregates of malformed protein “recruits” normal protein to change shape
may dislodge a chaperone to facilitate this process, creating a propagation sequence

Question 15

inheritance of familiar prion disease

Answer 15

autosomal dominant

Question 16

denatured malformed prion refolding

Answer 16

attains normal structure, b/c aa sequence is same as normal protein

Question 17

prion strains

Answer 17

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

Question 18

what is prion dz

Answer 18

normal aa sequence protein, coded from genome, misfolded into malignant form

Question 19

BSE v CJD

Answer 19

actually different strains, show up differently on gel

Question 20

annual incidence of neurodegenerative dz

Answer 20

AD 450,000
PD 50,000
ALS 5000
FTLD 2500
PSP 2000
MSA 1400
Prion 300

Question 21

financial cost of dementia

Answer 21

~1% of world GDP

Question 22

similarity of prion dz to AD

Answer 22

beta-amyloid can act like a malformed prion, but AD never shown to be infectious