Prions Flashcards
Insoluble aggregates of a specific protein fragment, high in β-sheet
Amyloid deposits
What is the characteristic histopathology of prions in the brain?
- ) Amyloid depositis
2. ) Vacuolar degeneration of tissue
The vacuolar degeneration of tissue is a subacute or transmissible
Spongiform encephalopathy
Classified as “slow virus” diseases. Sometimes take over 20 years to develop
Prion diseases
There is no inflammation in damaged tissue and no immune response in a
Prion disease
A human disease that can be transmitted by transplantation of tissue from an infected individual, or by use of contaminated medical instruments
Creutzfeldt-Jakob disease (CJD)
Prion disease of the Fore people of the highlands of Papua New Guinea, was transmitted by the ritual consumption, by family members, of brain tissue from deceased relatives
Kuru
A disease of sheep, named for the behavior of diseased animals, which scrape themselves against walls or trees. This is the best-studied form of prion disease
Scrapie
The recent prion epidemic among cattle in new england is termed
Bovine spongiform encephalopathy (Mad Cow Disease)
Transmission is by consumption of meat from infected animals, or of livestock feed derived from animal carcasses
Mad cow disease
Human mad cow disease acquired from contaminated beef is termed
Variant CJD (vCJD)
Believed to transport infections material from the digestive tract to brain, with amplification in secondary lymphoid organs
Macrophages
CJD, Kuru, and Scrapie are all forms of prion disease acquired from
Infection
What are the three prion diseases that are acquired from inheritance?
-All autosomal dominant
Gerstmann-Straussler-Scheinker (GSS) syndrome, Familial fatal insomnia (FFI), and Inherited Creutzfeldt-Jakob disease
This is the common (85%) form of CJD. The incidence is about one case per million persons per year, in all populations. Mean age of onset is about 65 years
Spontaneous prion disease
No bacterium, virus, fungus, or protozoan which produces prion disease has ever been cultured from infected tissue or visualized by light or
Electron microscopy
Are highly stable
Prion diseases
Contaminated material should be incinerated if possible. Otherwise the recommended procedure is a 1 hour soak in
1N NaOH
Purified preparations of infectious material contain a single protein with molecular weight 27-30 kd. This protein forms the
Amyloids in the brain
Recent experiments show that the most infectious fractions of brain tissue contain not the large amyloid aggregates but oligomers of
10-20 PrP molecules
The infectious agents of prion diseases have little or no
Nucleic acid
The protein of amyloid aggregates is encoded by the genome of the host. It is designated
PrP (Prion Protein)
A glycoprotein found on the extracellular face of neuron plasma membranes, anchored to the membrane by covalent linkage to a molecule of a phosphatidyl inositol glycolipid
PrP
Transcription of PrP and amino acid composition of PrP in infected and normal individuals are
Identical
Explains the lack of an immune response: PrP and its derivatives are normal constituents of the body, to which the immune system should be tolerant
The prion hypothesis
PrP fragments from the normal brain are rich in
α-helix (completely destroyed by proteases)
PrP fragments from the infected brain are rich in
β-sheet (resistant to proteases)
PrPC is in equilibrium with a rare, energetically unfavorable conformation, PrPC. PrPC principally reverts to PrPC but very rarely transforms to PrPSc. The altered conformation of PrPSc allows it to bind additional PrPC and catalyze its conversion to PrPSc. This is called
Prusiner’s hypothesis
This is an autocatalytic process: once it begins the rate of conversion of PrPC to PrPSc continuously increases. PrPSc is proteolytically cleaved and the cleaved protein aggregates into amyloid fibrils
Prusiner’s Hypothesis
Arises from rare spontaneous transformation of PrPC* to PrPSc
Sporadic prion disease
Initiated by introduction of PrPSc from an exogenous source, i.e. consumption in the diet, contact with contaminated surgical instruments, organ transplants
Infectious prion disease
Caused by mutations in the PrP gene. These increase the rate of spontaneous conversion of PrPC to PrPSc sufficiently that disease occurs in every person with the mutation
Inherited prion diseases
When disease is transmitted from one species to another, the protein which accumulates in brain plaques should be that encoded by the genome of the host, not the
Species of origin
A critical test of the Prion Hypothesis: PrPSc should convert
PrPC to PrPSC
Heritable prion-like conditions exist in
Yeast and other fungi
When disease is first transmitted from one species to another, the incubation time is longer than when the inoculum and the host are from the
Same species
PrP 27-30 from different forms of human prion disease leads to formation of forms of PrP that differ in electrophoretic mobility and distribution in the
Brain
If the infectious agent for prion diseases is a virus, then when compared to an ordinary virus, it must be far more
Stable
This virus would also have to be able to interact in some way with
PrP protein
All deaths from vCJD have been in persons homozygous for a specific allele of the human
PrP gene
vCJD occurs in young people in contrast to classic sporadic CJD, which occurs in the
Elderly
A prion disease of deer and elk, endemic in Colorado and Wyoming, which recently has begun to spread elsewhere
Chronic wasting disease
