PRION DISEASES

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PRION DISEASES

• D. H. Duckworth
• March 20, 2008

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Characteristics

• 1. Degenerative nervous system diseases with very
  long incubation periods (months to years
  decades)
• 2. No inflammatory response
• 3. Chronic progressive pathology (slow infection)
• 4. No remissions or recoveries always fatal
• 5. Degenerative histopathology amyloid
  plagues, gliosis
• 6. No visible virion-like structures by electron
  microscopy
• 8. No interferon production No interferon
  sensitivity
• 9. No infectious nucleic acid demonstrable
• 10. No antigenicity
• 11. No alteration in pathogenesis (incubation
  period, duration, course) by immunosuppression or
  immunopotentiation
• 12. No cytopathic effect in infected cells in
  vitro
• 13. Varying individual susceptibility to high
  infecting dose in some host species
  Unpredictable ability to cross species lines

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Definition

• Degenerative diseases of the central nervous
  system caused by a pathogenic isoform of a normal
  cell protein

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Scrapie

• Disease of sheep
• Known for at least 200 years
• Causes scraping of fleece, stumbling, behavioral
  changes
• Post mortem exams show loss of neurons in CNS

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Transmission of Scrapie

• Lambs from healthy flocks acquire the disease
  when exposed to scrapie flocks
• Route of transmission unknown
• Crosses species lines and infects goats
• No evidence of infection of humans

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Characteristics of Scrapie Agent

• Resistant to formaldehyde, ethanol, protease,
  heat to 100 degrees C.
• Resistant to nuclease, uv, ionizing radiation
• Co-purifies with normal sheep protein

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Kuru

• Disease of New Guinea natives
• Discovered by D. C. Gajdusek in 1957
• 100 mortality
• Experimentally transmitted to chimpanzees
• Transmitted by ritual cannibalism
• Many aspects of the disease mimic
  Creutzfeld-Jacob Disease

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Human Prion Diseases

• Kuru
• Creutzfeldt-Jakob Disease
• Genetic
• Sporadic
• Iatrogenic
• Gerstmann-Straussler-Scheinker Syndrome
• Fatal Familial Insomnia
• New Variant Creutzfeldt-Jakob Disease

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Animal Prion Diseases

• Scrapie
• Transmissible mink encephalopathy
• Chronic Wasting Disease (CWD)
• Bovine Spongiform Encephalopathy (BSE) aka Mad
  Cow Disease
• Feline spongiform encephalopathy

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BSE.Mad Cow Disease

• First appeared in England in 1985
• Approx 1 million cows infected in the following
  10 years
• Began to disappear after ruminant carcasses were
  banned in cattle feed

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nvCJD

• First appeared in 1994
• Patients had younger age of onset than CJD (29 vs
  60)
• Psychiatric symptoms were prominent
• Disease course is longer (survival is 14 mo vs 4
  mo for CJD)

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Relationship of Mad Cow to nvCJD

• All prions from nvCJD had distinctive patterns of
  disease in mice that were different from CJD
• Glycosylation patterns were similar in Western
  blotsdifferent from the patterns found in CJD
• Same patterns were found in BSE prions!
• Concluded that nvCJD transmitted to people by
  ingestion of meat from BSE cows

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Origin of Mad Cow Disease

• By feeding scrapie infected material from sheep
  to cows?
• Spontaneous mutation?
• Feed contaminated with human remains?

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Origin and Transmission of All Prion Diseases

• Scrapie mutation? Transmission unknown
• Mink encephalopathy feeding sick sheep to mink,
  transmission by feeding dead mink to mink
• CWD - ?
• BSE - feeding sick sheep to cattle, then feeding
  sick cattle to other cattle
• Feline spongiform encephalopathy feeding sick
  cattle to cats
• Kuru mutation? Transmitted by ritual
  cannibalism
• CJD mutation and ? Transmitted iatrogenically
• nvCJD feeding sick cows to humanshas not been
  transmitted?

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Prions Isoform of Normal Host Protein

• Normal Protein
• Protease sensitive
• Soluble
• High alpha-helix content
• Found in brain tissue

• Disease Causing Prion
• Protease resistant Insoluble
• Forms amyloid fibrils
• High beta-pleated sheet conformation

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How do Prions Replicate?

• When the normal prion protein changes shape it
  becomes pathogenic
• Mutations can occur that make the pathogenic
  shape more likely
• Prions dont replicate but they do increase in
  number
• When an abnormal prion combines with a normal
  one, the normal one changes it shape and becomes
  abnormalhence the numbers of abnormal prions
  increases, but it is at the expense of the normal
  ones. No new protein is created