Novel strain properties distinguishing sporadic prion diseases sharing prion protein genotype and prion type

In most human sporadic prion diseases the phenotype is consistently associated with specific pairings of the genotype at codon 129 of the prion protein gene and conformational properties of the scrapie PrP (PrP(Sc)) grossly identified types 1 and 2. This association suggests that the 129 genotype favours the selection of a distinct strain that in turn determines the phenotype. However, this mechanism cannot play a role in the phenotype determination of sporadic fatal insomnia (sFI) and a subtype of sporadic Creutzfeldt-Jakob disease (sCJD) identified as sCJDMM2, which share 129 MM genotype and PrP(Sc) type 2 but are associated with quite distinct phenotypes. Our detailed comparative study of the PrP(Sc) conformers has revealed major differences between the two diseases, which preferentially involve the PrP(Sc) component that is sensitive to digestion with proteases (senPrP(Sc)) and to a lesser extent the resistant component (resPrP(Sc)). We conclude that these variations are consistent with two distinct strains in sFI and sCJDMM2, and that the rarer sFI is the result of a variant strain selection pathway that might be favoured by a different brain site of initial PrP(Sc) formation in the two diseases.