Transmissible spongiform encephalopathies
prion proteins (PrP) are part of normal cellular function
metal metabolism
important fxn'l roles in nervous tissue
enriched along axons and terminals
present in most vertebrates
misfolded TSE forms
soluable
insoluable
proteinase K sensitive, can be broken down
proteinase K resistant
structure
a helices
small beta sheets
structure of stacked, clumped beta sheets
prion disease hypothesis
aa change creates misfolding event
PRP^res present
almost indestructable
shielded
catalyzes shape change in normal PrP
leads to transmissible spongiform encephalopathies
diseases
CWD
BSE
misfolded Prp^res spread through LN and nervous systems
begin to clump
fibrils
plaques
cellular death
limited immune/inflammatory response
body unable to recognize it as "foreign"
persists in environment
scrapie
contracted...
acquired
diet
eniornmental exposure
medical procedures
hereditary
autosomal dom
10-15% human cases
spontaneous
characteristics
prolonged incubation period
progressive debilitating neurological disease
100% fatal
diverse
most cases 3-5yo ewes
24mo with susceptible genotypes
signs
apprehenison
isolation
scraping
ataxia
weight loss
incoordination
95% of all cases in UK
associated ruminant-derived feed
some documented in USA
signs
behavior changes
ataxia
incubation period
cows 2-8y
humans - very long
emerging international dz
all cervids impacted
ID 300ng from neural tissue or saliva
no confirmed cases in humans
LN best diagnostic tissue
incubation 2+ years to death
signs
weight loss
increased drinking and urination
excessive drooling
fearlessness
loss of awareness
decreased social interaction
shedding prions the whole time
diagnostics
believed to be derived from scrapie
diagnostics
PMCA
microfluidic RT-QuIC
MNPRO facility at UMN
IHC