Abstract
BackgroundSporadic 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 (PrPSc) 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.ResultsIn 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 PrPSc and intermediate type PrPSc, which shows intermediate electrophoretic mobility between types 1 and 2 PrPSc. Modeling experiments using PrP-humanized mice indicated that MV2K contains a mixture of intermediate type PrPSc with the 129M genotype (Mi PrPSc) and type 2 PrPSc with the 129V genotype (V2 PrPSc) that originated from V2 PrPSc, whereas MV2C + K may also contain type 2 PrPSc with the 129M genotype and cortical pathology (M2C PrPSc) that lacks infectivity to the PrP-humanized mice in addition to Mi and V2 PrPSc.ConclusionsTaken together, the present study suggests that the phenotypic heterogeneity of MV2 stems from their different PrPSc origin(s).
Highlights
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 (PrPSc) in the brain
Creutzfeldt-Jakob disease (CJD) is a lethal transmissible neurodegenerative disease caused by an abnormal isoform of prion protein (PrPSc), which is converted from the normal cellular isoform (PrPC) [1]
Modelling of MV2 To resolve the complicated pathogenesis of MV2, we hypothesized that MV2 with kuru plaques (MV2K) might have originated from type 2 PrPSc with the 129V genotype and might contain V2 PrPSc and the intermediate type PrPSc with the 129M genotype, since we previously found that PrPC with the 129M genotype in Ki-Hu129M/M converted into Mi PrPSc after challenge with VV2 brain material containing V2 PrPSc
Summary
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 (PrPSc) 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. Since MV2 shows wide phenotypic variations, Parchi and colleagues have proposed dividing this heterogeneous entity based on histopathological criteria (MV2C showing a predominant cortical pathology or MV2K showing kuru type PrP amyloid plaques) [9]. MV2K + C is relatively common but sometimes misdiagnosed as MV2K even by experts of CJD surveillance centers [10] Besides these complicated histotypes, type 2 PrPSc in certain MV2 cases shows atypical features, i.e., wide, heterogeneous fragments that migrate at approximately 20 to 19 kDa and are sometimes visible as doublets [4,11,12]. The atypical type 2 PrPSc has not been recapitulated in an experimental transmission of MV2K to PrP-humanized mice carrying the 129M/V genotype [13]
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