Deciphering the pathogenesis of sporadic Creutzfeldt-Jakob disease with codon 129 M/V and type 2 abnormal prion protein

Background: Sporadic Creutzfeldt-Jakob disease is classified according to the genotype at polymorphic codon 129 (M or V) of the prion protein (PrP) gene and the type (1 or 2) of abnormal isoform of PrP (PrP Sc ) in the brain. The most complicated entity in the current classification system is MV2, since it shows wide phenotypic variations, i.e., MV2 cortical form (MV2C), MV2 with kuru plaques (MV2K), or a mixed form (MV2K + C). To resolve their complicated pathogenesis, we performed a comprehensive analysis of the three MV2 subgroups based on histopathological, molecular, and transmission properties. Results: In histopathological and molecular analyses, MV2C showed close similarity to MM2 cortical form (MM2C) and could be easily discriminated from the other MV2 subgroups. By contrast, MV2K and MV2K + C showed the same molecular type and the same transmission type, and the sole difference between MV2K and MV2K + C was the presence of cortical pathology characteristic of MV2C/MM2C. The remarkable molecular feature of MV2K or MV2K + C was a mixture of type 2 PrP Sc and intermediate type PrP Sc , which shows intermediate electrophoretic mobility between types 1 and 2 PrP Sc . Modeling experiments using PrP-humanized mice indicated that MV2K contains a mixture of intermediate type PrP Sc with the 129M genotype (Mi PrP Sc ) and type 2 PrP Sc with the 129V genotype (V2 PrP Sc ) that originated from V2 PrP Sc , whereas MV2C + K may also contain type 2 PrP Sc with the 129M genotype and cortical pathology (M2C PrP Sc ) that lacks infectivity to the PrP-humanized mice in addition to Mi and V2 PrP Sc . Conclusions: Taken together, the present study suggests that the phenotypic heterogeneity of MV2 stems from their different PrP Sc origin(s).