BSE agent hypotheses

Abstract

Although the oldest known form of transmissible spongiform encephalopathy (TSE), scrapie in sheep, has been described as early as in 1732, the nature of the agents causing TSEs still remains an enigma. Unusual properties of the agents, such as extreme resistance against UV, ionising radiation, and dry heat, already led to the term “unconventional virus”. From the number of hypotheses on the nature of these agents postulated, we will consider here three major ones only: virus, virino and prion. Present schools of thought, however, confine themselves mainly to the last two hypotheses. A recently formulated unified theory tries to reconcile the essentials of these two hypotheses. The virino hypothesis was called upon essentially to explain the variability in scrapie isolates when passaged in experimental rodents. Nucleic acids in a micro-organism would form the obvious explanation for such variability, but they have not been identified to date, even by using promising modern recombinant DNA methodologies. Research supporting the prion hypothesis has progressed steadily since its formulation. There was the discovery of the so-called prion protein (PrP), encoded by a single host gene. This PrP-gene is transcribed both in scrapie-infected animals and in normal animals. The resulting prion protein in its normal form was designated PrP C, meaning cellular PrP. The abnormal form, found in infected animals only, was designated PrP Sc meaning, scrapie PrP. The isoforms are not identical, though they seem to have the same primary structure. Supporters of both the virino and the prion hypothesis equally accept that PrP is a key element in the pathogenesis of these diseases. Proposed models, involving the conversion of the normal PrP C into PrP Sc as part of the pathogenesis, will be discussed. Further experimental support for the prion theory has recently been obtained through work with transgenic animals.