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Prion
Lecture Week 11
Medical Microbiology SBM 2044
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.
Human Prion Diseases
• Kuru
• Creutzfeldt-Jakob disease (CJD)
• Variant Creutzfeldt-Jakob disease (variant
CJD)
• Gerstmann-Straussler-Scheinker
syndrome (GSS)
• Fatal familial insomnia (FFI)
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
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
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
Diagnosing CJD
Magnetic resonance imaging of a patient with CreutzfeldtJacob disease. A. Increased signal intensity in the putamen and
head of the caudate (arrows). B. Bilateral parieto-occipital cortical
hyperintensity (arrows).
Diagnosing CJD
Pathologic specimen from a patient with CJD demonstrating
spongiform changes and neuronal loss.
Treatment and Prevention
• No specific treatment
• Prions are resistant to routine sterilization and
decontaminating procedures
• PrPSc can be activated by
– prolonged autoclaving (at 121°C 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
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
Epidemiology of CJD
Annual
frequency of
bovine
spongiform
encephalopathy
(BSE) and
variant CJD
(vCJD) in Great
Britain, 1988–
2003.
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
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! ! !)
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”).
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)
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
Quiz on all of the following topics:
1. Vaccines and Immunisations
2. Medical Diagnostics in Microbiology
3. Emerging and Reemerging Infectious
Diseases
4. Biological Weapons
5. Prions
•
•
Day/Date: Thursday 13th March 2008,
Time:
2:30-3:30pm
Happy studying!!