micro - prion mediated disease

prions

infectious proteins with NO genomic material

sporadic prion disease

spontaneousno known cause but may involve misfolding of normal protein

genetic prion disease

inherited defect in prion related protein

acquired prior disease

transmitted by infection due exposure (contaminated meats/tissues/instruments)

transmissible spongiform encephalopathies

degenerative disease of the CNS caused by prions

many spongiform encephalopathies are

inheritable

inheritbale TSEs

AlpersFatal familial insomniaGerstmann-Straussler

prion size

<100 microns (very small, will pass through filter)

prions do not have

nucleic acid genome

prions have extreme resistance to

heatdisinfectantsirradiation

prions are susceptible to high concentrations of

phenolperiodateNaOH (ROS)NaHOCl (ROS)

why do prions not fit Koch's postulates

CANNOT BE CULTURED

culturability of prions

can't be cultured (fail koch's postulates for this reason)

prions do not elicit

immune or inflammatory response

incubation period of prion disease

may be very long (up to 35 years)

CNS related symptoms of prion disease

loss of motor function and dementia --> coma and death

loss of motor function and dementia in prion disease results from

accumulation of insoluble amyloid plaques (feature of alzheimer's)

in prior disease, the aggregates of amyloid plaques result in

inhibition of intracellular signaling causing cell death and "holes" in brain

cases of iatrogenic CJD

surgical implements, EEG electrodes, dental tools

most common sources for prion transmission

corneal/dura mata graftscadaveric pituitary hormonepituitary gonadotropinblood banks

gene encoding cellular prion located on

chromosome 20

PrPc

normal cellular prion protein- glycoprotein

PrPsc

scrapie protein; abnormal protein that is infectious

PrPc location

surface of nerve cells in CNS (glycoprotein)

PrPsc directs the conversion of

PrPc to PrPsc

PrPsc acts as a

rogue chaperone protein (misguides other PrPc to fold incorrectly)- build up of new PrPsc contributes to buildup of mutant fibrils and plaques

normal structure of PrPc

appropriate alpha helices

altered structure of PrPsc

inappropriate beta pleated sheets

PrPsc has resistance to

proteinase K

proteinase K: PrPc and PrPsc

PrPc alpha helix configuration digested awayPsPsc beta pleated sheets provide resistance to enzymatic digestion

test for the detection of prion disease

NO definitive test

gold standard for confirmation of bovine spongiform encephalopathy (BSE)

necropsy of brain tissue

PrPres

partially proteinase resistant prion protein

PrPres may be detected using

immunohistochemistry

pathogenesis of acquired prion disease

ingested prion absorbed at peyer's patchesMALT phagocytizes prior particlestravel to other lymphoid tissuesenter CNS via innervation sites

ingested priors are absorbed across the gut wall at

peyer's patches

sporadic CJD patients deteriorate...

rapidly after symptoms begin

symptoms of sCJD

rapid deterioration- slurred speech- unsteady gait- myoclonic seizures- death

early sCJD may mimic

Alzheimer's

infectious human prion mediated disease

Kuru

animal prion diseases

scrapieBSECWD

kuru results from

fore tribe of cannibalsritual consumption of departed kin (brain eating)

kuru symptoms

fataldegeneration of cerebellum: ataxia, balance problemsdementiaparalysiswasting death within a year

at the time of death, it is estimated that how many people have sCJD

1 in 10,000

incidence of sCJD

1 per million per year

vCJD

Variant Creutzfeldt-Jakob disease

studies point to a link between vCJD and

BSE

CWD occurs in

cervids

cervids

deer, elk, moose

95% of BSE have occurred in

UK

how much US beef is tested for BSE

less than 5%

BSE circle of infection

refeeding of animal waste (from processing) right back to cattle - may have contributed to spread- banned in 2007

increased transmission of vCJD may be due to

consumption of infected beef

clinical signs of prion disease

ataxiadementiamyoclonus

CSF testing for prion disease

14-3-3 (nonspecific biomarker for brain injury)total tau (marker for neuronal injury)

definitive Dx of sCJD

neopathological diagnosis (myoclonus, ataxia, dementia)immunohistochemical confirmationtissue western blot for PrPresANTEMORTEM

probable Dx of sCJD

neuropsychiatric disorder + real time quaking induced conversion testorrapidly progressing dementia + 2 of following- myoclonus- visual/cerebellar signs- pyramidal or extrapyramidal signs- akinetic mutismPLUS EEG changes, a positive 14-3-3 test with disease less than 2 years, or MRI that doesn't indicate an alternative diagnosis

RT-QuIC

real time quaking induced conversion