The state of the prion

Abstract

Since the early 1950s researchers have been studying slow and invariably fatal diseases such as scrapie (sheep), Creutzfeldt–Jakob disease and kuru (humans), bovine spongiform encephalopathy (cattle and sheep) and chronic wasting disease (deer) that are now known to be caused by transmissible agents dubbed 'prions'. After decades of investigation the precise structure of the prion is still debated. The 'protein-only' hypothesis posits that prions are congruent with PrP^Sc, a misfolded form of the naturally occurring 'cellular prion protein' (PrP^C). PrP^C is encoded by the Prnp locus and is normally attached to the cell surface by a glycosylphosphatidyl inositol (GPI) anchor. Replication of the prion is attributed to PrP^Sc-catalysed conversion of PrP^C to PrP^Sc. The 'virus' and 'virino' hypotheses propose that the infectious agent contains an informational nucleic acid; however, despite the best efforts of many laboratories, no such molecule has been identified so far. Infectivity purified from infected brain material contains aggregates of PrP^Sc as the major protein component, bundled together with other substances including glycosaminoglycans and polysaccharides. Solubilization of the aggregates by denaturants causes loss of infectivity, which so far is irreversible. The replication of prions is discussed, together with experimental evidence obtained from whole organisms, cell lines and cell-free in vitro systems. Research into so-called 'yeast prions', self-propagating conformational isoforms of certain yeast proteins, has added experimental support to the protein-only hypothesis. Differences in strains and factors that affect prion transmission are considered in light of the protein-only prion hypothesis. Expression of cellular PrP is essential for susceptibility to prion disease and for prion replication, but other genes also have a modulating role. The spread of prions within organisms also requires expression of the cellular form PrP^C, both within and outside the central nervous system. Certain cells of the immune system serve as amplification sites in prion spread. The origin and evolution of prions are considered. Misfolded PrP may have evolved to serve a useful purpose and at the same time acquired a pathogenic potential that, in early evolutionary times, when the human life span was short, did not confer a selective disadvantage. Alternatively, prions could be derived from ancient exogenous pathogens that are now fully integrated into host chromosomes. More trivially, prions are misfolded proteins that by coincidence have the ability to invade a host through the digestive tract, make their way into the lymphoreticular system where they are amplified and transfer themselves into the central nervous system, which they then destroy.