According to this molecular typing system, sCJD is classified into six subgroups (MM1, MM2, MV1, MV2, VV1, or VV2)

According to this molecular typing system, sCJD is classified into six subgroups (MM1, MM2, MV1, MV2, VV1, or VV2). 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, em i.e. /em , 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 Corilagin 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 Corilagin different PrPSc origin(s). strong class=”kwd-title” Keywords: Creutzfeldt-Jakob disease, Prion protein, Classification, Humanized knock-in mouse Background 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]. There is a polymorphism (methionine, M; or valine, V) at codon 129 of the prion protein (PrP) gene. Parchi and colleagues reported that the codon 129 genotype (M/M, M/V, or V/V) and the type (type 1 or type 2) of PrPSc in the brain are major determinants of the clinicopathological phenotypes of sporadic Corilagin CJD (sCJD) [2-5]. Type 1 and type 2 PrPSc are distinguishable according to the size of the proteinase K (PK)-resistant core of PrPSc (21 and 19 kDa, respectively), reflecting differences in the PK-cleavage site (at residues 82 and 97, respectively) [6]. According to this molecular typing system, sCJD is classified into six subgroups (MM1, MM2, MV1, MV2, VV1, or VV2). In addition, MM2 can be divided into two subgroups based on histopathological criteria (MM2C, cortical form showing a predominant cortical pathology; or MM2T, thalamic form showing characteristic atrophy of thalamic and inferior olivary nuclei) [4]. This Parchis classification based on genotyping, PrPSc typing, and histotyping, has been widely used compared with an alternative classification system proposed by others [7,8]. Among the seven sCJD subgroups, the most complicated entity is MV2, which accounts for 11% of total sCJD [5]. 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]. Moreover, the co-occurrence of these histotypes in the same brain (denoted as MV2K?+?C) has also been reported [9]. MV2K is the most common subgroup in MV2 (8% of total sCJD Mouse monoclonal to CD38.TB2 reacts with CD38 antigen, a 45 kDa integral membrane glycoprotein expressed on all pre-B cells, plasma cells, thymocytes, activated T cells, NK cells, monocyte/macrophages and dentritic cells. CD38 antigen is expressed 90% of CD34+ cells, but not on pluripotent stem cells. Coexpression of CD38 + and CD34+ indicates lineage commitment of those cells. CD38 antigen acts as an ectoenzyme capable of catalysing multipe reactions and play role on regulator of cell activation and proleferation depending on cellular enviroment cases), whereas MV2C is very rare ( 0.5%) [5,9]. 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 Corilagin atypical features, em i.e. /em , 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 been reported in MV2K and MV2K?+?C but not in MV2C. The molecular mechanisms of the atypical type 2 PrPSc formation remain elusive. In addition, 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]. To characterize the MV2 subgroups in detail.