Prions are novel transmissible pathogens causing a group of invariably fatal neurodegenerative diseases that present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP).
Prion diseases of humans are referred to as Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), fatal familial insomnia (FFI), fatal sporadic insomnia (FSI), and kuru. In animals, the prion diseases are called scrapie of sheep and goats, bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD) of mule deer and elk, feline spongiform encephalopathy (FSE), and transmissible mink encephalopathy (TME).
Prions are devoid of nucleic acid and seem to be composed exclusively of a modified protein (disease-causing PrP isoform (PrPSc)) that is derived from the normal, cellular isoform (PrPC ). Through a posttranslational process, PrPC is refolded into PrPSc during which the protein acquires a high β-sheet content.
PrPC might function as a Cu(II) metalloprotein and may have a vital role in copper homeostasis.
Prion diseases are caused by the accumulation of PrPSc . In accord with the autosomal dominant inheritance of familial prion diseases caused by mutations of the PrP gene, PrPSc represents a gain of dysfunction.
The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammal in which it last replicated.
The length of the incubation time for infectious prion diseases is inversely proportional to the level of expression of PrPC and directly related to the level of protease-sensitive PrPSc . For a particular strain of prions, protease-resistant PrPSc accumulates to a given level in the central nervous system followed by the onset of neurologic dysfunction.
In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specified properties in the tertiary structure of PrPSc . Transgenetic studies argue that PrPSc acts as a template upon which PrPC is refolded into a nascent PrPSc molecule through a process facilitated by another protein.
The prion-like behavior of two yeast proteins whose phenotypes are transmitted nonchromosomally to their progeny has extended the generality of the prion concept.
Knowledge about prions has important implications for understanding the structural plasticity of proteins as well as a wide variety of degenerative diseases.