EVIDENCE FOR THE CONFORMATION OF THE PATHOLOGICAL ISOFORM OF THE PRION PROTEIN ENCIPHERING AND PROPAGATING PRION DIVERSITY

The fundamental event in prion diseases seems to be a conformational c hange in cellular prion protein (PrPC) whereby it is converted into th e pathologic isoform PrPSc. In fatal familial insomnia (FFI), the prot ease-resistant fragment of PrPSc after deglycosylation has a size of 1 9 kilodaltons, whereas that from other inherited and sporadic prion di seases is 21 kilodaltons. Extracts from the brains of FFI patients tra nsmitted disease to transgenic mice expressing a chimeric human-mouse PrP gene about 200 days after inoculation and induced formation of the 19-kilodalton PrPSc fragment, whereas extracts from the brains of fam iliar and sporadic Creutzfeldt-Jakob disease patients produced the 21- kilodalton PrPSc fragment in these mice. The results presented indicat e that the conformation of PrPSc functions as a template in directing the formation of nascent PrPSc and suggest a mechanism to explain stra ins of prions where diversity is encrypted in the conformation of PrPS c.