THEME 10: PRIONS & TSEs

Definition of prion

Infectious protein lacking nucleic acid

Origin of the term prion

PRotein Infection Only

Scientist who identified prions

Stanley Prusiner

Year prions were identified

1982

Nobel Prize related to prions

Prusiner received the Nobel Prize in Medicine in 1997

Key feature of prions

No associated DNA or RNA

Immune response to prions

Do not induce antibody production

Early evidence for protein-only hypothesis

Tikvah Alper showed infectivity resistant to radiation

Disease studied by Alper

Scrapie in sheep

Main protein involved in prion diseases

Prion protein (PrP)

Normal cellular prion protein

PrPc or PrPsen

Pathogenic prion protein

PrPSc or PrPres or PrP27-30

Secondary structure of PrPc

Rich in alpha-helices

Secondary structure of PrPSc

Rich in beta-sheets

Detergent solubility of PrPc

Soluble

Detergent solubility of PrPSc

Insoluble

Protease sensitivity of PrPc

Proteinase K sensitive

Protease sensitivity of PrPSc

Proteinase K resistant

Aggregation property of PrPc

Does not aggregate

Aggregation property of PrPSc

Forms aggregates

Resistance of PrPc to inactivation

Not resistant

Resistance of PrPSc to inactivation

Highly resistant to heat, pH and chemicals

Scrapie-associated fibers

Aggregated PrPSc fibrils

Mechanism of prion propagation

Conversion of PrPc into PrPSc

Pathological effect of prions

Neurodegeneration

Creutzfeldt-Jakob disease incidence

Approximately 1 case per million people

Typical age of CJD patients

50–70 years

Proportion of sporadic CJD

Approximately 85%

Proportion of familial CJD

Approximately 15%

Fatal Familial Insomnia (FFI)

Genetic human prion disease in central and southern Europe

Gerstmann-Sträusler-Scheinker disease (GSS)

Familial prion disease affecting ~50 families worldwide

Kuru disease origin

Linked to cannibalistic rituals

Population affected by Kuru

Fore population

Variant Creutzfeldt-Jakob disease (vCJD)

Linked to bovine spongiform encephalopathy

Number of vCJD cases since 1996

Approximately 229 cases

Main country affected by vCJD

United Kingdom

Typical age of vCJD patients

Young adults (~20 years)

Key pathological feature of vCJD

Florid plaques

Peripheral tissue involvement in vCJD

Widespread dissemination

Source of vCJD infection

Prion-contaminated feed

Iatrogenic prion disease

Caused by medical procedures

Number of iatrogenic prion cases

More than 400

Genetic susceptibility codon

Codon 129 of PRNP gene

High-risk genotype for prion disease

Methionine/Methionine (MM)

Protective genotypes

Methionine/Valine or Valine/Valine

Percentage of Caucasian population with MM genotype

Approximately 40%

Animal prion disease in sheep

Scrapie

Duration of scrapie presence

More than 200 years

Scrapie geographic distribution

Endemic in Europe

Scrapie resistant genotype

ARR/ARR

Scrapie susceptible genotype

VRQ/VRQ

Bovine spongiform encephalopathy (BSE)

Prion disease of cattle

BSE transmission route

Meat and bone meal

BSE tissue infectivity

Restricted mainly to CNS

Relationship between BSE and humans

Linked to vCJD

Chronic wasting disease (CWD)

Affects deer and elk

CWD geographic distribution

Endemic in USA

Transmission of CWD

Natural transmission

Peripheral dissemination in CWD

Yes, similar to scrapie

Environmental stability of prions

Highly resistant to degradation

Prion excretion routes

Biological fluids and feces

Environmental sources of prions

Slaughterhouse, hospital, urban wastewater

Technique for prion amplification

Protein Misfolding Cyclic Amplification (PMCA)

Principle of PMCA

Cyclic incubation and sonication to amplify PrPSc

Purpose of PMCA

Sensitive detection of pathological prions

Sample types for prion detection

Blood and cerebrospinal fluid

Main challenge in prion control

Extreme resistance to inactivation