title: Deciphering the pathogenesis of sporadic Creutzfeldt-Jakob disease with codon 129 M/V and type 2 abnormal prion protein.
abstract: 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 (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.
  
  
  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 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.
  
  
  CONCLUSIONS
  Taken together, the present study suggests that the phenotypic heterogeneity of MV2 stems from their different PrPSc origin(s).
authors.affiliation: Division of Neurological Science, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. kitamoto@med.tohoku.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Otsuka
authors.forename: Masahito
authors.initials: M
authors.lastname: Yamada
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Matsuura
authors.forename: Shirou
authors.initials: S
authors.lastname: Mohri
authors.forename: Tetsuyuki
authors.initials: T
authors.lastname: Kitamoto
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003062:Codon; D007562:Creutzfeldt-Jakob Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D055879:Gene Knock-In Techniques; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008822:Mice, Transgenic; D011110:Polymorphism, Genetic; D018620:PrPSc Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D003062:Codon; D018620:PrPSc Proteins