Molecular assessment of human susceptibility to bse and scrapie gregory raymond

The conversion of the normal protease-sensitive host prion protein (PrP-sen) to a disease specific protease-resistant isoform (PrP-res) is a key biochemical event that occurs in the pathogenesis of all transmissible spongiform encephalopathies (TSE's). We have developed a cell-free system in which PrP-sen is converted to PrP-res. The conversion efficiencies seem to be dependent upon the molecular compatibility of PrP-sen and PrP-res. The cell-free conversion efficiencies correlate remarkably well with known in vivo transmissibilities suggesting that this assay' could be useful as an indicator of the transmission potential between species. In the experiments reported here. we use this conversion system to gauge, at the molecular level, the potential transmissibility of scrapie (a TSE of sheep) and bovine spongiform encephalopathy (BSE. a TSE of cattle) to humans. We observed weak conversion of the normal human PrP-sen to the abnormal PrP-res isoform when incubated with PrP-res isolated from either scrapie-infected sheep (PrP-Sc) or BSE-infected cattle (PrP-BSE). However, the efficiencies of these heterologous conversion reactions were much lower than homologous human, bovine and sheep conversions. The similar but poor efficiency of PrP-BSE or PrP-Sc to convert normal human PrP-sen suggests that, at least at the molecular level, the inherent ability of these diseases to affect humans following exposure is likely to be finite, but similarly very low.