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• W4249697079 abstract "proteinaceous infectious particles and slow, or unconventional, viruses. Prions are the causative agents of the transmissible spongiform encephalopathies (TSEs). We owe mad cow disease (bovine spongiform encephalopathy; BSE) and the human equivalent, new variant Creutzfeldt–Jakob disease, to one strain of these infectious little molecules but the most common TSE by far is scrapie, a neurodegenerative affliction of sheep and goats. As far as we know, only mammals seem to be susceptible to these diseases. So, no mad chickens yet. Antarctic, fairy, thin-billed or broad-billed prions (South Atlantic seabirds) or the wreckfish (Polyprion americanus), sole member of the Polyprionidae. Yes, Reed Wickner, a yeast geneticist, does. His definition of the prion encompasses not only mammalian disease agents but also proteins that allow non-Mendalian inheritance of certain traits in yeast and fungi. But the term really belongs to Stan Prusiner of UCSF, winner of the 1998 Nobel Prize for Physiology or Medicine, who resurrected J.S. Griffiths' 1967 idea of an infectious protein. After years in the intellectual wilderness, he gave this idea the West Coast treatment, repackaged it as the ‘prion hypothesis’, and never looked back. Crucially, he also discovered a candidate protein, PrP, and a great deal else. In its most common form, PrPC, this 208-amino-acid glycoprotein is tethered to nerve cell membranes by a single glycolipid anchor. But it is also found in lymphoid tissue and, at relatively high concentrations, as a free-floating monomeric protein in blood. This form is not infectious, nor does it seem to cause any harm. It's PrPSc, the abnormal isoform of PrP, that does the damage. This is the form found associated with the disease, and the infectious agent, which is relatively insoluble and resistant to proteolysis. Not very. Perhaps they differ by only a minor twist or turn of their polypeptide chains but dogma has it the interchange of PrPC to PrPSc is self-perpetuating, with twisted PrPSc serving as a template for the demonic conversion of PrPC. The conversion can be produced in the test tube but it is not autocatalytic in vitro, and the ‘new PrPSc’ has not yet been shown to be infectious in vivo. NMR spectroscopy has given us a picture of PrPC but the structure of PrPSc and the mechanism of conversion remain unknown. Last year it was simpler. Now, the convenient criteria used to distinguish ‘non-infectious’ from ‘infectious’ — relative protease-resistance and insolubility — have been demolished. In one recent study, a ‘soluble’ PrPSc of 106 amino-acids was genetically engineered in transgenic mice. In another study, a highly infectious prion strain obtained from a patient with a rare human TSE (Gerstmann–Staussler–Scheinker syndrome) transmitted a TSE-like disease to mice without noticeably changing their normal prion protein. Confused? Join the growing club of people who now doubt the classical description of the infectious agent as ‘PrPSc, a proteinase-resistant protein’ and are looking for other factors. Who knows? The protein binds copper and might serve as a copper transport protein in the cellular response to oxidative stress. But it's one of the many proteins that can be ‘knocked-out’ in transgenic mice without gross adverse effects. The mice eat, drink and mate to their heart's content, although some have trouble sleeping and remembering things … typical research students, actually. But most critically, the mice can't develop prion diseases and they can't replicate the infectious agent. And, yes, someone has patented a PrP knockout cow, with a view to curbing BSE. Stan Prusiner (of course), Charles Weissmann and Adriano Aguzzi, but the word prion has been shunned by Alan Dickinson, discoverer of the murine prion protein gene, Sinc. With Hugh Fraser, he was the first to produce rigorous criteria for typing different strains of sheep scrapie agent. Their criteria are based on the brain pathology and incubation times generated by these scrapie strains in mice of differing Sinc genotypes. Their methods were also critical in showing that BSE and new variant CJD are caused by a similar strain of agent. The lack of a molecular explanation for the variety of TSE strains continues to be a thorn in the side of those who believe a single protein could be the infectious agent. Sadly, no. Pentosan sulphate seems to be the most promising prophylactic agent (in mice, that is) but no compound has yet been effective in humans. J Hope, Institute for Animal Health, Compton, Berkshire, RG20 7NN, UK." @default.
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• W4249697079 title "Prions" @default.
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• W4249697079 doi "https://doi.org/10.1016/s0960-9822(99)80435-7" @default.
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