Prions

PropertiesProperties

Distinctive characteristicsDistinctive characteristics

DiseasesDiseases

Properties Small, filterable infectious particles that contain

protein but no detectable nucleic acid. Prion proteins (PrPC) are encoded by the host

genome. PrPC is found in neuronal synapses, binds copper,

has unknown function. Prion proteins become infectious and pathogenic

(PrPSc) as a result of protein conformational changes.

PrPSc can catalyze its own formation from PrPC in animals.

PrPSc aggregates and accumulates in diseased brain.

Prions

Diseases Chronic, progressive, invariably fatal central nervous

system degeneration. Brain pathology is spongiform encephalopathy—large

vacuoles in cortex and cerebellum give brain a sponge-like appearance.

Affected areas contain microscopic insoluble amyloid fibrils and macrocrystalline arrays known as amyloid plaques.

No signs of a host immune response. Can arise spontaneously or by ingestion of infected tissue. Affects wild and domesticated ruminants (sheep and goats:

scrapie; cattle: mad cow disease); mink, cats. Experimentally transferred to mice, hamsters, chimpanzees.

Prions

Distinctive characteristics Proteinaceous infectious agent that contains no

nucleic acid and consists only of a single species of protein called PrP.

A new kind of infectious agent that can transmit a disease and replicate itself without the intervention of informational nucleic acids.

Prions

Prions are proteins that cause fatal brain diseases

Prion diseases were first detected in domestic ruminants

BSE, mad cow disease Scrapie in sheep, goat

Human prion diseases can be either inherited or transmitted

Prions

Prions

The infectious agent of prion diseases contains protein but no detectable nucleic acid

PrPSc is encoded by a host cell gene

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Fig. 30.3 Domains and modifications of the prion protein.

Differences between PrPC and PrPSc

Proteinase K treatment of PrPSc gives a proteinase-resistant 27–30 kilodalton core fragment (PrP 27–30) (missing N-terminal aa 23-89) that retains infectivity

PrPSc tends to form oligomers and aggregates detected as fibrils in infected brains

the conformational change from PrPC to PrPSc could involve formation of -helix structure

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Fig. 30.6 -helical model of PrP 27–30.

Top (a) and side views (b), respectively, of PrP 27–30 modeled with theN-terminal portion of the protein as a left-handed –helix (ribbon arrows displayed in a triangular barrel). The structure of the -helical part (ribbon helices) was derived from the known strucure of the C-terminal region of PrPC.

The prion hypothesis: formation of infectious and pathogenic prions from normal PrPC

Preexisting Prpc is required to propagate infectious prions and cause prin disease

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Is the prion hypothesis correct?

Pathology and diagnosis of prion diseases Tissue abnormalities (insoluble amyloid fifers) of

prion disease are confined to CNS

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Genetics of prion diseases Encoded by a single exon of unique gene Heterozygosity at 129 protects against both

inherited and infectious prion disease

Prion diseases are not usually transmitted among different species

Prion infectivity depends on sequence similarity between donor and recipient prion proteins

But species barrier is not absolute

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Strain variation and crossing of the species barrier

Human cases of new varient CJD appear to linked to the BSE epidemic in the UK

New varient CJD is distinct from sporadic CJD, caused by different prion strain, less restricted by species barrier

Protein pattern of nvCJD is similar to that of BSE-infected animals

The nature of the prion infectious agent Prions are transmissible, replicable, and variable

disease-causing agents that are distinct from viruses.

Whether we define them as “living” or “nonliving” or as an “infectious enzyme,” we do know the following about them:

(1) they have arisen in organisms during evolution

(2) they are able to propagate themselves and the diseases they cause

(3) they appear to be able to evolve and to adapt themselves to different hosts.

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Key Terms

Amyloid BSE Chlorpromazine Creutzfeldt-Jakob disease (CJD) Dendritic cells Dura mater Kuru

Mad cow disease New variant Creutzfeldt-Jakob

disease (nvCJD or vCJD) Prion Prion disease Quinacrine Scrapie Spongiform encephalopathy Transgene