Allelic origin of the abnormal prion protein isoform in familial prion diseases

The hallmark of prion diseases is the presence of an aberrant isoform of the prion protein (PrPres) that is insoluble in nondenaturing detergents and resistant to proteases. We investigated the allelic origin of PrPres in brains of subjects heterozygous for the D178N mutation linked to fatal familial insomnia (FFI) and a subtype of Creutzfeldt-Jakob disease (CJD(178)), as well as for insertional mutations associated with another CJD subtype. We found that in FFI and CJD(178) subjects, only mutant PrP was detergent-insoluble and protease-resistant. Therefore, PrPres derives exclusively from the mutant allele carrying the D178N mutation. In contrast, in the CJD subtype harboring insertional mutations, wild-type PrP was also detergent-insoluble and likely to be protease-resistant. Our findings indicate that the participation of the wild-type PrP in the formation of PrPres depends on the type of mutations, providing an insight into the molecular mechanisms underlying the phenotypic heterogeneity in familial prion diseases.