Evidence for the Conformation of the Pathologic Isoform of the Prion Protein Enciphering and Propagating Prion Diversity

Abstract

The fundamental event in prion diseases seems to be a conformational change in cellular prion protein (PrP^C) whereby it is converted into the pathologic isoform PrP^Sc. In fatal familial insomnia (FFI), the protease-resistant fragment of PrP^Sc after deglycosylation has a size of 19 kilodaltons, whereas that from other inherited and sporadic prion diseases is 21 kilodaltons. Extracts from the brains of FFI patients transmitted disease to transgenic mice expressing a chimeric human-mouse PrP gene about 200 days after inoculation and induced formation of the 19-kilodalton PrP^Sc fragment, whereas extracts from the brains of familial and sporadic Creutzfeldt-Jakob disease patients produced the 21-kilodalton PrP^Sc fragment in these mice. The results presented indicate that the conformation of PrP^Sc functions as a template in directing the formation of nascent PrP^Sc and suggest a mechanism to explain strains of prions where diversity is encrypted in the conformation of PrP^Sc.