Transmissible spongiform encephalopathy

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs),^[1] are a group of progressive, incurable, and invariably fatal conditions that are associated with the degeneration of the nervous system in many animals, including humans, cattle, and sheep. Strong evidence now supports the once unorthodox hypothesis that prion diseases are transmitted by abnormally shaped protein molecules known as prions.^[2][3] Prions consist of a protein called the prion protein (PrP).^[2] Misshapen PrP (often referred to as PrP^Sc) conveys its abnormal structure to naive PrP molecules by a crystallization-like seeding process. Because the abnormal proteins stick to each other, and because PrP is continuously produced by cells, PrP^Sc accumulates in the brain, harming neurons and eventually causing clinical disease.^[2][4][3]

Prion diseases are marked by mental and physical deterioration that worsens over time.^[5][6] A defining pathologic characteristic of prion diseases is the appearance of small vacuoles in the various parts of the central nervous system that create a sponge-like appearance when brain tissue obtained at autopsy is examined under a microscope.^[2][3] Other changes in affected regions include the buildup of PrP^Sc, gliosis, and the loss of neurons.^[7]

In non-human mammals, the prion diseases include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle (popularly known as "mad cow disease") chronic wasting disease (CWD) in deer and elk, and others.^[8] prion diseases of humans include Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia, kuru, and variably protease-sensitive prionopathy.^[6][9] Creutzfeldt-Jakob disease has been divided into four subtypes: sporadic (sCJD), hereditary/familial (fCJD), iatrogenic (iCJD) and variant (vCJD). These diseases form a spectrum of related conditions with overlapping signs and symptoms.

Prion diseases are unusual in that their aetiology may be genetic, infectious, or sporadic.^[2] Genetic (inherited) prion diseases result from rare mutations in PRNP, the gene that codes for PrP (see Genetics, below). Unlike conventional infectious diseases, which are spread by agents with a DNA or RNA genome (such as viruses or bacteria), prion diseases are transmitted by prions, the active material of which is solely abnormal PrP. Infection can occur when the organism is exposed to prions through ingestion of infected foodstuffs or via iatrogenic means (such as treatment with biologic material that had been inadvertently contaminated with prions).^[10] The variant form of Creutzfeldt–Jakob disease in humans is caused by exposure to BSE prions.^[11][12][13] Whereas the naturally occurring transmission of prion diseases among nonhuman species is relatively common, prion transmission to humans is very rare; rather, the majority of human prion diseases are sporadic (idiopathic) in nature^[14] (see Infectivity, below). Sporadic prion diseases occur in the absence of a mutation in PrP or a source of infection.

Although research has shown that the infectious capacity of prions is encoded in the conformation of PrP^Sc,^[2][4] it is likely that auxilliary components contribute to their formation and/or infectivity. Purified PrP^C appears to be unable to convert to the infectious PrP^Sc form in a protein misfolding cyclic amplification (PMCA) assay unless other components are added, such as a polyanion (usually RNA) and lipids. These other components, termed cofactors, may form part of the infectious prion, or they may serve as catalysts for the replication of a protein-only prion.^[15] Considering that the cofactors can be produced by chemical synthesis instead of being sourced solely from infected cases (or any animal at all), it is fair to say that they do not form the infectious part of the prion. However, these catalysts (especially the polyanion) do have a tendency to be included in the prion aggregate, which makes seeding new aggregates easier in vitro.^[16][17]