Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by CHCHD2
Abstract Parkinson's disease (PD) is a common neurodegenerative disorder that results from the loss of dopaminergic neurons. Mutations in coiled‐coil‐helix‐coiled‐coil‐helix domain containing 2 (CHCHD2) gene cause a familial form of PD with α‐Synuclein aggregation, and we here identified the pa...
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Springer Nature
2023-08-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202317451 |
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| author | Satoru Torii Satoko Arakawa Shigeto Sato Kei‐ichi Ishikawa Daisuke Taniguchi Hajime Tajima Sakurai Shinya Honda Yuuichi Hiraoka Masaya Ono Wado Akamatsu Nobutaka Hattori Shigeomi Shimizu |
| author_facet | Satoru Torii Satoko Arakawa Shigeto Sato Kei‐ichi Ishikawa Daisuke Taniguchi Hajime Tajima Sakurai Shinya Honda Yuuichi Hiraoka Masaya Ono Wado Akamatsu Nobutaka Hattori Shigeomi Shimizu |
| author_sort | Satoru Torii |
| collection | DOAJ |
| description | Abstract Parkinson's disease (PD) is a common neurodegenerative disorder that results from the loss of dopaminergic neurons. Mutations in coiled‐coil‐helix‐coiled‐coil‐helix domain containing 2 (CHCHD2) gene cause a familial form of PD with α‐Synuclein aggregation, and we here identified the pathogenesis of the T61I mutation, the most common disease‐causing mutation of CHCHD2. In Neuro2a cells, CHCHD2 is in mitochondria, whereas the T61I mutant (CHCHD2T61I) is mislocalized in the cytosol. CHCHD2T61l then recruits casein kinase 1 epsilon/delta (Csnk1e/d), which phosphorylates neurofilament and α‐Synuclein, forming cytosolic aggresomes. In vivo, both Chchd2T61I knock‐in and transgenic mice display neurodegenerative phenotypes and aggresomes containing Chchd2T61I, Csnk1e/d, phospho‐α‐Synuclein, and phospho‐neurofilament in their dopaminergic neurons. Similar aggresomes were observed in a postmortem PD patient brain and dopaminergic neurons generated from patient‐derived iPS cells. Importantly, a Csnk1e/d inhibitor substantially suppressed the phosphorylation of neurofilament and α‐Synuclein. The Csnk1e/d inhibitor also suppressed the cellular damage in CHCHD2T61I‐expressing Neuro2a cells and dopaminergic neurons generated from patient‐derived iPS cells and improved the neurodegenerative phenotypes of Chchd2T61I mutant mice. These results indicate that Csnk1e/d is involved in the pathogenesis of PD caused by the CHCHD2T61I mutation. |
| format | Article |
| id | doaj-art-171e40dcebbe419cb1dfbf178948b2a9 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-171e40dcebbe419cb1dfbf178948b2a92024-11-10T12:37:52ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-08-0115912010.15252/emmm.202317451Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by CHCHD2Satoru Torii0Satoko Arakawa1Shigeto Sato2Kei‐ichi Ishikawa3Daisuke Taniguchi4Hajime Tajima Sakurai5Shinya Honda6Yuuichi Hiraoka7Masaya Ono8Wado Akamatsu9Nobutaka Hattori10Shigeomi Shimizu11Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU)Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU)Department of Neurology, School of Medicine, Juntendo UniversityDepartment of Neurology, School of Medicine, Juntendo UniversityDepartment of Neurology, School of Medicine, Juntendo UniversityDepartment of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU)Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU)Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University (TMDU)Department of Clinical Proteomics, National Cancer Center Research InstituteCenter for Genomic and Regenerative Medicine, School of Medicine, Juntendo UniversityDepartment of Neurology, School of Medicine, Juntendo UniversityDepartment of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU)Abstract Parkinson's disease (PD) is a common neurodegenerative disorder that results from the loss of dopaminergic neurons. Mutations in coiled‐coil‐helix‐coiled‐coil‐helix domain containing 2 (CHCHD2) gene cause a familial form of PD with α‐Synuclein aggregation, and we here identified the pathogenesis of the T61I mutation, the most common disease‐causing mutation of CHCHD2. In Neuro2a cells, CHCHD2 is in mitochondria, whereas the T61I mutant (CHCHD2T61I) is mislocalized in the cytosol. CHCHD2T61l then recruits casein kinase 1 epsilon/delta (Csnk1e/d), which phosphorylates neurofilament and α‐Synuclein, forming cytosolic aggresomes. In vivo, both Chchd2T61I knock‐in and transgenic mice display neurodegenerative phenotypes and aggresomes containing Chchd2T61I, Csnk1e/d, phospho‐α‐Synuclein, and phospho‐neurofilament in their dopaminergic neurons. Similar aggresomes were observed in a postmortem PD patient brain and dopaminergic neurons generated from patient‐derived iPS cells. Importantly, a Csnk1e/d inhibitor substantially suppressed the phosphorylation of neurofilament and α‐Synuclein. The Csnk1e/d inhibitor also suppressed the cellular damage in CHCHD2T61I‐expressing Neuro2a cells and dopaminergic neurons generated from patient‐derived iPS cells and improved the neurodegenerative phenotypes of Chchd2T61I mutant mice. These results indicate that Csnk1e/d is involved in the pathogenesis of PD caused by the CHCHD2T61I mutation.https://doi.org/10.15252/emmm.202317451CHCHD2Csnk1e/dα‐Synuclein |
| spellingShingle | Satoru Torii Satoko Arakawa Shigeto Sato Kei‐ichi Ishikawa Daisuke Taniguchi Hajime Tajima Sakurai Shinya Honda Yuuichi Hiraoka Masaya Ono Wado Akamatsu Nobutaka Hattori Shigeomi Shimizu Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by CHCHD2 EMBO Molecular Medicine CHCHD2 Csnk1e/d α‐Synuclein |
| title | Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by CHCHD2 |
| title_full | Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by CHCHD2 |
| title_fullStr | Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by CHCHD2 |
| title_full_unstemmed | Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by CHCHD2 |
| title_short | Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by CHCHD2 |
| title_sort | involvement of casein kinase 1 epsilon delta csnk1e d in the pathogenesis of familial parkinson s disease caused by chchd2 |
| topic | CHCHD2 Csnk1e/d α‐Synuclein |
| url | https://doi.org/10.15252/emmm.202317451 |
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