Prion

Lecture Week 11Medical 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 Creutzfeldt-Jacob 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 Immunisations2. Medical Diagnostics in Microbiology3. Emerging and Reemerging Infectious

Diseases4. Biological Weapons5. Prions

• Day/Date: Thursday 13th March 2008,• Time: 2:30-3:30pm

Happy studying!!