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).
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