Your browser doesn't support javascript.
loading
Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by CHCHD2.
Torii, Satoru; Arakawa, Satoko; Sato, Shigeto; Ishikawa, Kei-Ichi; Taniguchi, Daisuke; Sakurai, Hajime Tajima; Honda, Shinya; Hiraoka, Yuuichi; Ono, Masaya; Akamatsu, Wado; Hattori, Nobutaka; Shimizu, Shigeomi.
Affiliation
  • Torii S; Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Arakawa S; Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Sato S; Department of Neurology, School of Medicine, Juntendo University, Tokyo, Japan.
  • Ishikawa KI; Department of Neurology, School of Medicine, Juntendo University, Tokyo, Japan.
  • Taniguchi D; Center for Genomic and Regenerative Medicine, School of Medicine, Juntendo University, Tokyo, Japan.
  • Sakurai HT; Department of Neurology, School of Medicine, Juntendo University, Tokyo, Japan.
  • Honda S; Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Hiraoka Y; Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Ono M; Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Akamatsu W; Laboratory of Genome Editing for Biomedical Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • Hattori N; Department of Clinical Proteomics, National Cancer Center Research Institute, Tokyo, Japan.
  • Shimizu S; Center for Genomic and Regenerative Medicine, School of Medicine, Juntendo University, Tokyo, Japan.
EMBO Mol Med ; 15(9): e17451, 2023 09 11.
Article in En | MEDLINE | ID: mdl-37578019
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.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Parkinson Disease / Casein Kinase 1 epsilon Type of study: Etiology_studies / Prognostic_studies Limits: Animals Language: En Journal: EMBO Mol Med Journal subject: BIOLOGIA MOLECULAR Year: 2023 Document type: Article Affiliation country: Japan Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Parkinson Disease / Casein Kinase 1 epsilon Type of study: Etiology_studies / Prognostic_studies Limits: Animals Language: En Journal: EMBO Mol Med Journal subject: BIOLOGIA MOLECULAR Year: 2023 Document type: Article Affiliation country: Japan Country of publication: United kingdom