prions
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Definition: Prions are infectious proteins.
In mammals, prions reproduce by recruiting normal cellular prion protein (PrPC) and stimulating its conversion to the disease-causing (scrapie) isoform (PrPSc).
A major feature that distinguishes prions from viruses is that PrPSc is encoded by a chromosomal gene. Limited proteolysis of PrPSc produces a smaller, protease-resistant molecule of approximately 142 amino acids, designated PrP 27–30, which polymerizes into amyloid.
The polypeptide chains of PrPC and PrPSc are identical in composition but differ in their three-dimensional, folded structures (conformations).
PrPC is rich in alpha-helixes (spiral-like formations of amino acids) and has little beta-sheet (flattened strands of amino acids), whereas PrPSc is less rich in alpha-helixes and has much more beta-sheet.
There is evidence that PrPC has three alpha-helixes and two short beta-strands; in contrast, a plausible model suggests that PrPSc may have only two alpha-helixes and more beta-strands.
This structural transition from alpha-helixes to beta-sheet in PrP is the fundamental event underlying prion diseases.
Four new concepts have emerged from studies of prions:
First, prions are the only known example of infectious pathogens that are devoid of nucleic acid. All other infectious agents possess genomes composed of either RNA or DNA that direct the synthesis of their progeny.
Second, prion diseases may be manifested as infectious, genetic, or sporadic disorders. No other group of illnesses with a single cause has such a wide spectrum of clinical manifestations.
Third, prion diseases result from the accumulation of PrPSc, which has a substantially different conformation from that of its precursor, PrPC.
Fourth, PrPSc can have a variety of conformations, each of which seems to be associated with a specific disease.
How a particular conformation of PrPSc is imparted to PrPC during replication in order to produce a nascent PrPSc with the same conformation is unknown. The factors that determine the site in the central nervous system where a particular PrPSc is deposited are also not known.
Strains of Prions
The existence of prion strains raises the question of how heritable biologic information can be encrypted in a molecule other than nucleic acid.
Strains of prions have been defined by the rapidity with which they cause central nervous system disease and by the distribution of neuronal vacuolation.
Patterns of PrPSc deposition have also been used to characterize these strains.
There is mounting evidence that the diversity of prions is enciphered in the conformation of the PrPSc protein.
Studies involving the transmission of fatal familial insomnia and familial Creutzfeldt–Jakob disease to mice expressing a chimeric human–mouse PrP transgene have shown that the tertiary and quaternary structure of PrPSc contains strain-specific information.
Studies of patients with fatal sporadic insomnia have extended these findings, making it clear that PrPSc acts as a template for the conversion of PrPC into nascent PrPSc.
See also
prion diseases
transmissible spongiform encephalopathies
Creutzfeldt-Jakob disease
References
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