Wednesday 29 October 2003
Definition: Prions are infectious proteins.
Prions are apparently composed of abnormal forms of a host protein, termed prion protein (PrP). These agents cause transmissible spongiform encephalopathies, including kuru (associated with human cannibalism), Creutzfeldt-Jakob disease (CJD; associated with corneal transplants), bovine spongiform encephalopathy (BSE; better known as mad cow disease), and variant Creutzfeldt-Jakob disease (vCJD; likely transmitted to humans from BSE-infected cattle).
PrP is normally found in neurons. Diseases occur when the prion protein undergoes a conformational change that confers resistance to proteases. The protease-resistant PrP promotes conversion of the normal protease-sensitive PrP to the abnormal form, explaining the infectious nature of these diseases.
Accumulation of abnormal PrP leads to neuronal damage and distinctive spongiform pathologic changes in the brain. Spontaneous or inherited mutations in PrP, which make PrP protease resistant, have been observed in the sporadic and familial forms of CJD, respectively.
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.
transmissible spongiform encephalopathies
Aguzzi A, Heikenwalder M, Polymenidou M. Insights into prion strains and neurotoxicity. Nat Rev Mol Cell Biol. 2007 Jul;8(7):552-61. PMID: 17585315
True HL. The battle of the fold: chaperones take on prions. Trends Genet. 2006 Feb;22(2):110-7. PMID: 16378656
Dimcheff DE, Portis JL, Caughey B. Prion proteins meet protein quality control. Trends Cell Biol. 2003 Jul;13(7):337-40. PMID: 12837603
Aguzzi A, Montrasio F, Kaeser PS. Prions: health scare and biological challenge. Nat Rev Mol Cell Biol. 2001 Feb;2(2):118-26. PMID: 11252953
Collinge J. Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci. 2001;24:519-50. PMID: 11283320
Collinge J. Human prion diseases and bovine spongiform encephalopathy (BSE). Hum Mol Genet. 1997;6(10):1699-705. PMID: 9300662