5-Prime | Prions - The Terminators
What are they? The prion protein (PrP) is a widely expressed, membrane-associated protein transcribed from the PRNP gene, which is highly conserved among mammals. PrPs exist in two forms: a common, harmless alpha-helical form, and a rare beta-sheet form that causes fatal mammalian brain diseases such as scrapie, Creutzfeld-Jacob disease, and mad cow disease. Prion diseases collectively are called spongiform encephalopathies, causing sponge-like vacuoles in the brain. Symptoms include dementia and ataxia.
What do normal PrPs do? That function is still unknown, although they may be involved in response to oxidative stress. Glycosylation, which occurs in various complex combinations, may play an important role in prion function and pathogenicity.
How does a prion disease develop? The harmful form of the PrP can simply occur stochastically (in about one in a million people per year), or as the result of mutations (spontaneous or inherited); through infection, such as from eating infected meat or from exposure to contaminated surgical instruments; or as the result of mutations, either spontaneous or inherited. About 15% of cases are hereditary; sporadic cases seem to occur largely in people homozygous for a specific PRNP allele. Prions are the protein world's equivalent of "The Terminator," resisting many methods of degradation, including high heat.
How did prions become known? Their existence was the subject of long and hard debate. Prions are infectious proteins, but this concept violated biology's DNA-to-RNA-to-protein dogma, because the protein appears to be self-replicating, without DNA or RNA to carry genetic information. In other words, with prions, protein-to-protein is a valid pathway. Prion diseases are transmissible because, like molecular bad apples, the mere presence of the harmful form similarly corrupts normal PrPs. Although the process can occur in vitro, it occurs more efficiently in cells, presumably facilitated by cofactors or chaperones.
Who proved that prions are proteins? Stanley Prusiner, who won the Nobel Prize for his prion work, showed that the infectious agent in scrapie, a spongiform encephalopathy found in sheep, could not be deactivated by methods that destroy DNA. Therefore, it couldn't be a virus or bacterium, but it was sensitive to proteases. Even after Prusiner received the prize in 1997, a few dissenters still maintained that the evidence for infectious prions is circumstantial, and that small viruses coated by prion proteins (virinos) could be the cause of disease.