- Open Access
Deciphering the pathogenesis of sporadic Creutzfeldt-Jakob disease with codon 129 M/V and type 2 abnormal prion protein
© Kobayashi et al.; licensee BioMed Central Ltd. 2013
Received: 8 November 2013
Accepted: 10 November 2013
Published: 13 November 2013
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.
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.
Taken together, the present study suggests that the phenotypic heterogeneity of MV2 stems from their different PrPSc origin(s).
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) . 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 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) . 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) . This Parchi’s 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 . 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) . Moreover, the co-occurrence of these histotypes in the same brain (denoted as MV2K + C) has also been reported . MV2K is the most common subgroup in MV2 (8% of total sCJD 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 . 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 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 .
To characterize the MV2 subgroups in detail and to resolve their complicated pathogenesis, we performed a comprehensive analysis of the MV2 subgroups based on histopathological, molecular and transmission properties.
CJD cases included in this study were patients with clinically, genetically and histopathologically proven sCJD. Brain tissues were obtained at autopsy from CJD patients after receiving informed consent for research use. The diagnosis of sCJD, histotype, and PrPSc type were confirmed by PrP immunohistochemistry and western blot analysis [14, 15]. The genotype and the absence of mutations in the open reading frame of the PrP gene were determined by sequence analysis as described . According to Parchi’s classification [4, 5], these sCJD cases were classified as follows: MM1, 1 case; MM2C, 1 case; VV2, 1 case; MV2C, 1 case; MV2K, 1 case; and MV2K + C, 1 case. These patients showed the typical phenotypes of each sCJD subgroup in the clinicopathological and biochemical examinations. Ethical approval for these studies was obtained from the Ethical Committee of Tohoku University Graduate School of Medicine. All experiments carried out on humans were in compliance with the Helsinki Declaration.
Brain homogenates (10%) were prepared as described . Intracerebral transmission to PrP-humanized mice was performed using 20 μl of the homogenates . The production of the knock-in mice expressing human PrP with the 129M/M genotype (Ki-Hu129M/M), Ki-Hu129M/V, and Ki-Hu129V/V has been reported [17, 18]. The expression levels of human PrP in the brains of these knock-in mice were identical to the level observed in wild-type mouse. The inoculated mice were sacrificed after the onset of disease or at death. One hemisphere of the brain was fixed in 10% buffered formalin for immunohistochemistry, and the other hemisphere was immediately frozen for western blotting. Ethical approval for these experiments using mice was obtained from Animal Care and Use Committee of Tohoku University Graduate School of Medicine.
Formalin-fixed brain tissues were treated with formic acid (99% for human tissues or 60% for mouse tissues) for 1 hour to inactivate the infectivity, and embedded in paraffin. Tissue sections were pretreated by hydrolytic autoclaving before PrP immunohistochemistry . The anti-PrP monoclonal antibodies 3F4  and #71 [20, 21] were used as the primary antibodies for human sections, and anti-PrP antiserum PrP-N  was used as the primary antibody for mouse sections. Goat-anti-mouse immunoglobulin polyclonal antibody labelled with the peroxidase-conjugated dextran polymer, EnVision + (Dako) and anti-rabbit EnVision + were used as the secondary antibodies. For the quantification of PrP plaques in the patient brains, at least six representative digital microscopy images were taken at 10× magnification from each brain region and analyzed using ImageJ software (rsb.info.nih.gov/ij). The number of PrP plaques was manually counted, and the mean plaque density in each brain region was calculated.
PrPSc was extracted from human or mouse brains with collagenase treatment as described . For deglycosylation of PrPSc, samples were digested with PNGaseF (New England Biolabs) as reported . Protein samples were subjected to SDS-PAGE using 15% Tris-glycine long gels of 15 cm length and western blotting . Type 1 PrPSc- and type 2 PrPSc-specific polyclonal antibodies (designated as Tohoku 1 (T1) and Tohoku 2 (T2), respectively ) and the 3F4 antibody were used as the primary antibodies. Anti-rabbit EnVision + and anti-mouse EnVision + were used as the secondary antibodies. The signal intensities of the western blots were quantified with Quantity One software using an imaging device VersaDoc 5000 (Bio-Rad Laboratories).
Incubation times and the signal intensities of PrPSc bands are expressed as mean ± SEM.
Histotyping and molecular typing of MV2.
Next we performed western blot analysis of PrPSc in the brains of three MV2 subgroups using PrPSc type-specific antibodies and a conventional anti-PrP antibody 3F4 that detects all PrPSc types. Type 1 PrPSc-specific antibody Tohoku 1 (T1) recognizes epitopes between residues 82 and 96 that are retained in type 1 PrPSc but not in type 2 PrPSc after PK-digestion. In addition, the epitopes for the T1 antibody are also retained in the intermediate type PrPSc showing intermediate electrophoretic mobility between types 1 and 2 PrPSc, which is observed in a part of dura mater-graft associated CJD . Type 2 PrPSc-specific antibody Tohoku 2 (T2) specifically detects the N-terminal PK-cleavage site of type 2 PrPSc (at residue 97) . In the conventional western blot analysis using the anti-PrP antibody 3F4, MV2K and MV2K + C had heterogeneous unglycosylated bands located at 20 kDa to 19 kDa as reported (Figure 1e) . Since the upper unglycosylated band migrated faster compared with type 1 PrPSc from MM1, these heterogeneous bands were different from the co-occurrence of types 1 (21 kDa) and 2 (19 kDa) PrPSc. In contrast, MV2C and MM2C had only type 2 PrPSc located at 19 kDa. In the western blot analysis using the PrPSc type-specific antibodies, MV2K and MV2K + C had large amounts of T1-reactive PrPSc in addition to T2-reactive PrPSc (Figure 1f). The amounts of T1-reactive PrPSc in the MV2K cerebrum were relatively low compared with the cerebellum, suggesting regional variability in the ratio of the amounts of T1-reactive PrPSc to the amounts of T2-reactive PrPSc. The low amounts of T1-reactive PrPSc in the MV2K cerebrum accounted for the absence of the 20 kDa (upper) unglycosylated band in the western blot using the 3F4 antibody, since conventional western blot analysis using antibodies that react with all PrPSc types cannot detect a coexisting minority component . In addition, the T2-reactive PrPSc in the cerebellum of MV2K or MV2K + C consisted of ladder-like multiple fragments, which were quite different from the T2-reactive PrPSc in the cerebrum. Thus, MV2K and MV2K + C showed similar molecular properties in the western blot analysis using the PrPSc type-specific antibodies. By contrast, MV2C and MM2C had predominant T2-reactive PrPSc with only trace amounts of T1-reactive PrPSc as reported [26, 27]. MM1 had predominant T1-reactive PrPSc with trace amounts of T2-reactive PrPSc as reported . Taken together, MV2C was clearly different from the other MV2 subgroups in the molecular typing as well, whereas MV2K and MV2K + C could not be distinguished by molecular typing even with the PrPSc type-specific antibodies.
Transmission typing of MV2
Modelling of MV2
To resolve the complicated pathogenesis of MV2, we hypothesized that MV2K might have originated from type 2 PrPSc with the 129V genotype (denoted as V2 PrPSc) and might contain V2 PrPSc and the intermediate type PrPSc with the 129M genotype (denoted as Mi PrPSc), 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. These Mi PrPSc showed striking similarity to the 20 kDa PrPSc in MV2K or MV2K + C [25, 29, 31]. Meanwhile, MV2K + C might also contain type 2 PrPSc with the 129M genotype and cortical pathology (denoted as M2C PrPSc) in addition to Mi and V2 PrPSc, since MV2C showed close similarity to MM2C that contains M2C PrPSc, as described above.
Next we performed intracerebral inoculation of MM2C brain material containing M2C PrPSc into the PrP-humanized mice to gain insight into the reason why MV2K + C (containing M2C, Mi, and V2 PrPSc) and MV2K (containing Mi and V2 PrPSc) could not be distinguished by transmission typing. As expected, none of the MM2C-inoculated mice had developed disease by the end of their life span. An accumulation of PrPSc was absent in the brains of the MM2C-inoculated mice (Additional file 2: Figure S2). Thus, M2C PrPSc lacked infectivity to the PrP-humanized mice.
We performed a comprehensive analysis of the MV2 subgroups, i.e., MV2C, MV2K, and MV2K + C, and resolved their complicated pathogenesis. MV2C showed close similarity to MM2C in the histopathological and molecular analyses 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. The remarkable molecular feature of MV2K or MV2K + C was a mixture of the intermediate type PrPSc and type 2 PrPSc. To model MV2K, we inoculated VV2 brain material containing V2 PrPSc into the PrP-humanized mice with the 129M/V genotype. These mice showed widespread PrP plaques and the accumulation of a mixture of the intermediate type PrPSc with the 129M genotype (Mi PrPSc) and V2 PrPSc in the brain. These results suggest that MV2K contains Mi and V2 PrPSc that originated from V2 PrPSc. In addition, we also inoculated MM2C brain material containing M2C PrPSc into the PrP-humanized mice to gain insight into the reason why MV2K and MV2K + C could not be distinguished by transmission typing. These transmission experiments revealed that M2C PrPSc lacked infectivity to the PrP-humanized mice. Therefore, the present data lead us to surmise that MV2K + C may also contain M2C PrPSc lacking infectivity to the PrP-humanized mice in addition to Mi and V2 PrPSc. Further study will be needed to verify that MV2C and MM2C are identical in transmission typing as well as histotyping and molecular typing. To grasp the whole picture of the phenotypic variability and PrPSc strain diversity in the MV2 subgroups, a transmission study of MV2C is in progress using the PrP-humanized mice.
Refined nomenclature for the MV2 subgroups a
Codon 129 genotype
MVi + 2
i + 2 g
Mi + V2
MV2K + C
MVi + 2C
i + 2
K + C
M2C + V2
M2C + Mi + V2
The generation of multiple PrPSc strains in heterozygotes of the PrP genotypes can result in a long incubation period due to interference among coexisting heterologous PrPSc, designated as heterozygous inhibition [34, 35]. In the present study, V2 PrPSc-inoculated Ki-Hu129M/V produced Mi and V2 PrPSc and showed longer incubation times compared with those of Ki-Hu129M/M despite its expression of PrPC with the 129V genotype, which is an optimal substrate for V2 PrPSc. Therefore, the long clinical course of MVi + 2 or MVi + 2C  may also be due to heterozygous inhibition among the coexisting Mi and V2 (and M2C) PrPSc.
Despite the coexistence of Mi and V2 PrPSc, MVi + 2 showed the same transmission properties as those of VV2 containing V2 PrPSc alone, as reported . This result is consistent with our previous findings that Mi PrPSc was originated from V2 PrPSc and showed the same transmission properties as those of the parental V2 PrPSc . Meanwhile, MVi + 2C containing M2C, Mi, and V2 PrPSc also showed the same transmission properties as those of VV2, since M2C PrPSc lacked infectivity to the PrP-humanized mice and did not affect the transmission properties of the coexisting Mi and V2 PrPSc. Thus, the transmission type does not reflect all existing PrPSc strains if their origins are identical or if they lack infectivity to experimental animals. Nevertheless, transmission typing will remain indispensable for the risk assessment of PrPSc infection among the PrP genotypes.
It remains unclear why M2C PrPSc lacked infectivity to the PrP-humanized mice despite the fact that they could propagate in the MM2C/MV2C patient brain. Although there was no evidence of successful transmission in the present study, very low infectivity of M2C PrPSc was reported in a transmission study using other PrP-humanized knock-in mouse lines . The disease duration of MM2C/MV2C patients is the longest among sCJD subgroups , suggesting slow propagation of M2C PrPSc. Therefore, M2C PrPSc may replicate less efficiently and take a longer time to propagate compared with the other PrPSc strains.
Dura mater graft-associated CJD with kuru plaques (p-dCJD) might be caused by infection of V2 PrPSc and/or Mi PrPSc to individuals with the 129M/M genotype. We reported previously that transmission of VV2 to animals with the 129M/M genotype caused p-dCJD like phenotype, i.e., widespread PrP plaques and an accumulation of Mi PrPSc, and that the transmission properties of p-dCJD were identical to those of VV2 . It has been reported that the transmission properties of MVi + 2 were the same as those of VV2 [13, 36]. In the present study, the transmission properties of MVi + 2C were also identical to those of VV2, and the transmission of MVi + 2 or MVi + 2C to animals with the 129M/M genotype caused p-dCJD like phenotype. These results suggest that p-dCJD is caused by infection of V2 PrPSc and/or Mi PrPSc from sCJD patients with VV2, MVi + 2, or MVi + 2C. Indeed, the incidence rate of p-dCJD among total dura mater graft-associated CJD is 32% , which is close to the sum total of the incidence of VV2 (15%), MVi + 2 (8%), and MVi + 2C (3%) in sCJD . Since Mi PrPSc in individuals with the 129M/M genotype has never been observed in sCJD patients, it might be a characteristic fingerprint of the infection of V2 PrPSc and/or Mi PrPSc to the 129M/M individuals.
The present study resolves the complicated pathogenesis of MV2. The phenotypic heterogeneity of MV2 stems from their different PrPSc origin(s).
We thank Y. Ishikawa, H. Kudo, M. Yamamoto, and A. Yamazaki for their excellent technical assistance, and B. Bell for critical review of the manuscript. This study was supported by Grants-in-Aid from the Ministry of Health, Labor and Welfare of Japan (Y.I., M.Y., S.M., and T.K.), Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (A.K. and T.K.), and a grant for TSE research from the Ministry of Health, Labor and Welfare of Japan (H23-Shokuhin-Ippan-005) (T.K.).
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