Prion

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Prion

• Lecture Week 11
• Medical Microbiology SBM 2044

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Prion Diseases

• Prion diseases are associated with the
  accumulation in the CNS of an abnormal form of a
  host protein called the prion protein, PrP
• Infectious agent an abnormally folded,
  degradation-resistant form of the PrP protein
• The disease is rare, fatal and rapidly
  progressive neurodegenerative diseases that occur
  in humans and other animal species
• They share common recognisable neuropathologic
  features
• presence of small vacuoles within the neuropil,
  produces a spongiform appearance,
• neuronal loss,
• glial cell proliferation.

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Human Prion Diseases

• Kuru
• Creutzfeldt-Jakob disease (CJD)
• Variant Creutzfeldt-Jakob disease (variant CJD)
• Gerstmann-Straussler-Scheinker syndrome (GSS)
• Fatal familial insomnia (FFI)

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Prions

• Proteinaceous infectious particle small
  infectious agent that consists of protein but
  lacks nucleic acid
• PrP is a host protein, and the sole constituents
  of prions
• The gene encoding PrP is found in the genomes of
  all humans and animals
• expressed in most human tissues, mainly in the
  CNS
• Function of PrP ? ?
• copper-binding protein, in cellular response to
  oxidative stress
• long-term memory

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PrPSc

• PrPSc is a pathological protease-resistant form
  of PrP
• First isolated from the brains of animals with
  scrapie
• Prion diseases PrP ? PrPSc
• a conformational change in PrP from a
  predominantly ?-helical form to ?-sheet

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CJD

• 1 case per 1 million population worldwide each
  year
• Sporadic disease
• Age at onset usually 55-65 years old
• Mean survival of 5 months
• Britain patients in their 20s variant CJD?
• Clinical manifestations
• Rapidly progressive dementia and myoclonus,
• memory loss, judgment difficulties
• cognitive disturbances
• death within 1 year

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Diagnosing CJD
Magnetic resonance imaging of a patient with
Creutzfeldt-Jacob disease. A. Increased signal
intensity in the putamen and head of the caudate
(arrows). B. Bilateral parieto-occipital cortical
hyperintensity (arrows).
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Diagnosing CJD
Pathologic specimen from a patient with CJD
demonstrating spongiform changes and neuronal
loss.
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Treatment and Prevention

• No specific treatment
• Prions are resistant to routine sterilization and
  decontaminating procedures
• PrPSc can be activated by
• prolonged autoclaving (at 121C and 15 psi for 4
  ½ hours
• immersion in 1 N NaOH (for 30 mins, repeat 3x)
• Prohibition on ruminant-derived products for all
  animal feed

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Variant CJD

• Bovine-to-human transmission of bovine spongiform
  encephalopathy (BSE), known as mad cow disease.
• PrP proteins show different glycosylation pattern
  and electrophoretic mobility, than other prion
  diseases
• Appear in the late 1990s, following epizootic of
  BSE in Britain
• may be caused by changes in the rendering
  process of bovine byproducts, use for cattle feed
  (cannibalism)
• Average age at onset 30 years old, a mean
  survival of 14 months

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Epidemiology of CJD
Annual frequency of bovine spongiform
encephalopathy (BSE) and variant CJD (vCJD) in
Great Britain, 19882003.
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Damaging Effects of vCJD

• Clinical manifestations depend of the locations
  of PrPSc accumulation in the NS
• All forms of CJD are uniformly fatal
• vCJD patients have
• prominent sensory disturbances (on the face,
  limbs and torso)
• psychiatric symptoms depression
• apathy, anxiety, intermittent delusions and
  psychosis
• abnormalities of gaze

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Diagnosing vCJD

• Laboratory and imaging studies are unhelpful
• CSF shows no cells, mild elevation of CSF protein
• MRI can be normal. But many patients present with
  signal hyperintensity in the pulvinar
• Presence of plaques which stain for PrPSc
  throughout cerebrum and cerebellum, basal ganglia
  and thalamus
• PrPSc has also been identified in tonsil biopsy
  tissue (nonneural tissue! ! !)

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Diagnosing vCJD
FIGURE Magnetic resonance imaging of a patient
with variant CJD. A. Increased signal intensity
in the pulvinar (pulvinar sign). B. Increased
signal intensity in the pulvinar and dorsomedial
thalamus (hockey stick sign).
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Other Human Prion diseases

• Gerstmann-Straussler-Scheinker syndrome (GSS)
• autosomal dominant pattern of inheritance
• progressive cerebellar degeneration accompanied
  by dementia
• Fatal familial insomnia (FFI)
• rapidly fatal midlife disease
• a mean survival of 13 months
• progressive insomnia, often with a dreamlike
  confusional state during waking hours
• inattention, memory loss, confusion,
  hallucinations
• myoclonus, ataxia and spasticity in later stage
  of disease
• dysautonomia (hyperhidrosis, hyperthermia,
  tachycardia and hypertension) and endocrine
  disturbances (? adrenocorticotropic hormone
  secretion, ?cortisol secretion)

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Review of the Course Content

• Microbes Man interactions Week 1-3
• Medical Bacteriology Week 4-6
• Medical Virology Week 7-10
• Medical Mycology Week 11-12
• Emerging infectious diseases biological
  agents of warfare Week 13
• Introduction to the medical
  diagnostics in microbiology Week 14

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Quiz on all of the following topics

• Vaccines and Immunisations
• Medical Diagnostics in Microbiology
• Emerging and Reemerging Infectious Diseases
• Biological Weapons
• Prions
• Day/Date Thursday 13th March 2008,
• Time 230-330pm
• Happy studying!!