Prions

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Prions
Properties
Diseases
Distinctive characteristics
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Prions

• 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.

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Prions

• Diseases
• Chronic, progressive, invariably fatal central
  nervous system degeneration.
• Brain pathology is spongiform encephalopathylarge
  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.

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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.

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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

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Prions
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Prions

• The infectious agent of prion diseases contains
  protein but no detectable nucleic acid
• PrPSc is encoded by a host cell gene

Fig. 30.3 Domains and modifications of the prion
protein.
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Prions

• Differences between PrPC and PrPSc
• Proteinase K treatment of PrPSc gives a
  proteinase-resistant 2730 kilodalton core
  fragment (PrP 2730) (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 b-helix structure

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Prions
Top (a) and side views (b), respectively, of PrP
2730 modeled with the N-terminal portion of the
protein as a left-handed bhelix (ribbon arrows
displayed in a triangular barrel). The structure
of the a-helical part (ribbon helices) was
derived from the known strucure of the C-terminal
region of PrPC.
Fig. 30.6 b-helical model of PrP 2730.
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Prions

• 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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Prions

• 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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Prions

• 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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Prions

• 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

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Prions

• 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

• Mad cow disease
• New variant Creutzfeldt-Jakob disease (nvCJD or
  vCJD)
• Prion
• Prion disease
• Quinacrine
• Scrapie
• Spongiform encephalopathy
• Transgene

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