Species Specificity in the Cell-Free Conversion of Prion Protein to Protease-Resistant Forms: A Model for the Scrapie Species Barrier

Scrapie is a transmissible neurodegenerative disease that appears to result from an accumulation in the brain of an abnormal protease-resistant isoform of prion protein (PrP) called PrPsc. Conversion of the normal, protease-sensitive form of PrP (PrPc) to protease-resistant forms like PrPschas been demonstrated in a cell-free reaction composed largely of hamster PrPcand PrPsc. We now report studies of the species specificity of this cell-free reaction using mouse, hamster, and chimeric PrP molecules. Combinations of hamster PrPcwith hamster PrPscand mouse PrPcwith mouse PrPscresulted in the conversion of PrPcto protease-resistant forms. Protease-resistant PrP species were also generated in the nonhomologous reaction of hamster PrPcwith mouse PrPsc, but little conversion was observed in the reciprocal reaction. Glycosylation of the PrPcprecursors was not required for species specificity in the conversion reaction. The relative conversion efficiencies correlated with the relative transmissibilities of these strains of scrapie between mice and hamsters. Conversion experiments performed with chimeric mouse/hamster PrPcprecursors indicated that differences between PrPcand PrPscat residues 139, 155, and 170 affected the conversion efficiency and the size of the resultant protease-resistant PrP species. We conclude that there is species specificity in the cell-free interactions that lead to the conversion of PrPcto protease-resistant forms. This specificity may be the molecular basis for the barriers to interspecies transmission of scrapie and other transmissible spongiform encephalopathies in vivo.