Online Module: Prions Flashcards
Recognize the clinical hallmarks of slow neurodegenerative diseases caused by prions
Degeneration of CNS, invariably progressing to ataxia, dementia, and death
Amyloid deposits (insoluble aggregates of a specific protein fragment, high in beta-sheet)
Vacuolar degeneration of tissue: “subacute or transmissible spongiform encephalopathies”
Long incubation period (in some cases, over 20 years)
No inflammation in damaged tissue
No immune response
Unusual features of the infectious agent
Unusual features because no bacterium, virus, fungus, or protozoan which produces prion disease has ever been cultured from infected tissue or visualized by light or electron microscopy
High stability: conventional disinfection does not inactivate it (need to incinerate contaminated material)
Unusual composition: Purified preparations of infectious material contain a single protein with molecular weight 27-30 kD - this protein forms the amyloid in brains of diseased individuals
Little or no nucleic acid
Note: b/c the infectious agent seems to contain only protein, termed prion for “proteinaceous infectious agent” - protein itself is the infectious agent
Describe the structure of the prion protein.
Designated PrP (“Prion Protein”)
PrP = glycoprotein found on extracellular face of neuron plasma membranes, anchored to the membrane by covalent linkage to a molecule of a phosphatidyl inositol glycolipid
Transcription of PrP gene is identical in normal and diseased brains.
AA sequences of PrP from normal and infected brains are identical.
PrP exists in different conformations in health and disease. In both normal and diseased brain tissue, proteolytic cleavage of PrP produces a fragment of 209 amino acids.
However, fragments from normal and diseased brain have different properties: Fragments from normal brain (PrP-C) are rich in alpha-helix and completely destroyed by proteases. Fragments from diseased brain (PrP-Sc) are rich in beta-sheet and highly resistant to proteases.
After protease treatment, a protease-resistant core of about 142 aa remain = PrP 27-30 –> this forms the amyloid in the brain
Characterize the three ways prion disease can be transmitted
By Infection, most frequently by the oral route
By Inheritance, with an autosomal dominant pattern
Spontaneously (“sporadic disease”)
By infection,
- Creutzfeldt-Jakob Disease (CJD) - human disease that can be transmitted by transplantation of tissue from an infected individual, or by use of contaminated medical instruments
- Kuru, 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
- Scrapie - diseased sheep scrape themselves against walls or trees (recent epidemic among cattle = Mad Cow Disease); transmission occurs by consumption of meat from infected animals, or livestock feed derived from animal carcasses; Human disease acquired from contaminated beef is termed variant Creutzfeldt-Jakob disease (vCJD)
Macrophages = believed to transport infectious material from digestive tract to brain, with amplification in secondary lymphoid organs; infectious material is present principally in lymphoid and nervous tissue, and inflammation promotes its accumulation at other sites
By Inheritance,
Well-characterized examples:
- Gerstmann-Strausller-Scheinker (GSS) syndrome
- Familial fatal insomnia (FFI)
- Inherited Creutzfeldt-Jakob Disease
Spontaneously (“sporadic disease”)
Common (85%) form of CJD
Incidence is about one case per million persons per year, in all populations
Mean age of onset is about 65 years
What is the prion hypothesis?
Explains the lack of an immune response - PrP and its derivatives = normal constituents of the body, to which the immune system should be tolerant
How could a protein be an infectious agent?
Prusiner’s hypothesis
- Spontaneous converesion of PrP-C to PrP-Sc
- PrP-Sc catalyses conversion of more PrP-C
- Proteolysis of PrP-Sc to PrP 27-30
- Cleaved PrP 27-30s aggregate into amyloid fibrils
Note: these PrP accumulations occur in other neurodegenerative diseases (Alzheimer’s, Parkinson’s, Amyotrophic lateral sclerosis)
The prion hypothesis predicts that:
- Sporadic prion diseases arises from rare spontaneous transformation of PrP-C to PrP-Sc (late onset reflects low probability of conversion and long incubation period)
- Infectious prion disease is initiated by introduction of PrP-Sc from an exogenous source (consumption in the diet, contact with contaminated surgical instruments, organ transplants)
- Inherited prion diseases are caused by mutations in the PrP gene. These increase the rate of spontaneous conversion of PrP-C to PrP-Sc sufficiently that disease occurs in every person with the mutation
Complexities of the prion hypothesis
- Incubation time effects and the “species barrier”
- “Strains” of PrP
- 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. –> aka, the catalyst and substrate react more slowly when from different species, more rapidly when from 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 after infection of mice –> thus, PrP-Sc would have to exist in MULTIPLE conformations, each capable of converting PrP-C to its own form
Therapy for prion diseases?
Antibodies specific for PrP-Sc can prevent accumulation of PrP aggregates, both in cell culture and in living mice
