Protease-resistant and detergent-insoluble prion protein is not necessarily associated with prion infectivity

PrPSc, an abnormal isoform of PrPC, is the only known component of the prio n, an agent causing fatal neurodegenerative disorders such as bovine spongi form encephalopathy (BSE) and Creutzfeldt-Jakob disease (CJD). It has been postulated that prion diseases propagate by the conversion of detergent-sol uble and protease-sensitive PrPC molecules into protease-resistant and inso luble PrPSc molecules by a mechanism in which PrPSc serves as a template. W e show here that the chemical chaperone dimethyl sulfoxide (Me2SO) can part ially inhibit the aggregation of either PrPSc or that of its protease-resis tant core PrP27-30. Following; Me2SO removal by methanol precipitation, sol ubilized PrP27-30 molecules aggregated into small and amorphous structures that did not resemble the rod configuration observed when scrapie brain mem branes were extracted with Sarkosyl and digested with proteinase K. Interes tingly, aggregates derived from Me2SO-solubilized PrP27-30 presented less t han 1% of the prion infectivity obtained when the same amount of PrP27-30 i n rods was inoculated into hamsters. These results suggest that the convers ion of PrPC into protease-resistant and detergent-insoluble PrP molecules i s not the only crucial step in prion replication. Whether an additional req uirement is the aggregation of newly formed proteinase K-resistant PrP mole cules into uniquely structured aggregates remains to be established.