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 r esult from an accumulation in the brain of an abnormal protease-resist ant isoform of prion protein (PrP) called PrPsc. Conversion of the nor mal, protease-sensitive form of PrP (PrPc) to protease-resistant forms like PrPsc has been demonstrated in a cell-free reaction composed lar gely-of hamster PrPc and PrPsc, We now report studies of the species s pecificity of this cell-free reaction using mouse, hamster, and chimer ic PrP molecules, Combinations of hamster PrPc with hamster PrPsc and mouse PrPc with mouse PrPsc resulted in the conversion of PrPc to prot ease-resistant forms, Protease-resistant PrP species were also generat ed in the nonhomologous reaction of hamster PrPc with mouse PrPsc, but little conversion was observed in the reciprocal reaction, Glycosylat ion of the PrPc precursors was not required for species specificity in the conversion reaction, The relative conversion efficiencies correla ted with the relative transmissibilities of these strains of scrapie b etween mice and hamsters, Conversion experiments performed with chimer ic mouse/hamster PrPc precursors indicated that differences between Pr Pc and PrPsc at residues 139, 155, and 170 affected the conversion eff iciency and the size of the resultant protease-resistant PrP species. We conclude that there is species specificity in the cell-free interac tions that lead to the conversion of PrPc to protease-resistant forms, This specificity may be the molecular basis for the barriers to inter species transmission of scrapie and other transmissible spongiform enc ephalopathies in vivo.