{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T11:18:21Z","timestamp":1793013501171,"version":"4.5.0"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"23","license":[{"start":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T00:00:00Z","timestamp":1570665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Scientific Research","award":["2586076"],"award-info":[{"award-number":["2586076"]}]},{"name":"Scientific Research","award":["18K15463"],"award-info":[{"award-number":["18K15463"]}]},{"name":"Scientific Research","award":["23129506"],"award-info":[{"award-number":["23129506"]}]},{"name":"Scientific Research","award":["25129707"],"award-info":[{"award-number":["25129707"]}]},{"name":"Scientific Research","award":["25461291"],"award-info":[{"award-number":["25461291"]}]},{"name":"Scientific Research","award":["15KK0354"],"award-info":[{"award-number":["15KK0354"]}]},{"name":"Scientific Research","award":["16K09676"],"award-info":[{"award-number":["16K09676"]}]},{"name":"Scientific Research","award":["17H04049"],"award-info":[{"award-number":["17H04049"]}]},{"name":"Scientific Research","award":["18K15465"],"award-info":[{"award-number":["18K15465"]}]},{"name":"Scientific Research","award":["18H04043"],"award-info":[{"award-number":["18H04043"]}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007428","name":"Naito Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007132","name":"Otsuka Pharmaceutical","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007132","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research Center Network for Realization Research Centers\/Projects of Regenerative Medicine"},{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"publisher","award":["JP17bm0804003"],"award-info":[{"award-number":["JP17bm0804003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Practical Research Project for Rare\/Intractable Diseases","award":["JP17ek0109244"],"award-info":[{"award-number":["JP17ek0109244"]}]},{"name":"Advanced Genome Research and Bioinformatics Study to Facilitate Medical Innovation","award":["JP19km0405206s0104"],"award-info":[{"award-number":["JP19km0405206s0104"]}]},{"name":"Research Project for Practical Applications of Regenerative Medicine","award":["JP16bk0104033"],"award-info":[{"award-number":["JP16bk0104033"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mutations in CHCHD2 are linked to a familial, autosomal dominant form of Parkinson\u2019s disease (PD). The gene product may regulate mitochondrial respiratory function. However, whether mitochondrial dysfunction induced by CHCHD2 mutations further yields \u03b1-synuclein pathology is unclear. Here, we provide compelling genetic evidence that mitochondrial dysfunction induced by PD-linked CHCHD2 T61I mutation promotes \u03b1-synuclein aggregation using brain autopsy, induced pluripotent stem cells (iPSCs) and Drosophila genetics. An autopsy of an individual with CHCHD2 T61I revealed widespread Lewy pathology with both amyloid plaques and neurofibrillary tangles that appeared in the brain stem, limbic regions and neocortex. A prominent accumulation of sarkosyl-insoluble \u03b1-synuclein aggregates, the extent of which was comparable to that of a case with \u03b1-synuclein (SNCA) duplication, was observed in CHCHD2 T61I brain tissue. The prion-like activity and morphology of \u03b1-synuclein fibrils from the CHCHD2 T61I brain tissue were similar to those of fibrils from SNCA duplication and sporadic PD brain tissues. \u03b1-Synuclein insolubilization was reproduced in dopaminergic neuron cultures from CHCHD2 T61I iPSCs and Drosophila lacking the CHCHD2 ortholog or expressing the human CHCHD2 T61I. Moreover, the combination of ectopic \u03b1-synuclein expression and CHCHD2 null or T61I enhanced the toxicity in Drosophila dopaminergic neurons, altering the proteolysis pathways. Furthermore, CHCHD2 T61I lost its mitochondrial localization by \u03b1-synuclein in Drosophila. The mislocalization of CHCHD2 T61I was also observed in the patient brain. Our study suggests that CHCHD2 is a significant mitochondrial factor that determines \u03b1-synuclein stability in the etiology of PD.<\/jats:p>","DOI":"10.1093\/hmg\/ddz241","type":"journal-article","created":{"date-parts":[[2019,10,4]],"date-time":"2019-10-04T11:34:06Z","timestamp":1570188846000},"page":"3895-3911","source":"Crossref","is-referenced-by-count":74,"title":["Mutations in CHCHD2 cause \u03b1-synuclein aggregation"],"prefix":"10.1093","volume":"28","author":[{"given":"Aya","family":"Ikeda","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenya","family":"Nishioka","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongrui","family":"Meng","sequence":"first","affiliation":[{"name":"Department of Neurodegenerative and Demented Disorders, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Takanashi","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwao","family":"Hasegawa","sequence":"first","affiliation":[{"name":"University Center of Legal Medicine, Kanagawa Dental University, Kanagawa 238-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Inoshita","sequence":"first","affiliation":[{"name":"Department of Treatment and Research in Multiple Sclerosis and Neuro-intractable Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kahori","family":"Shiba-Fukushima","sequence":"first","affiliation":[{"name":"Department of Treatment and Research in Multiple Sclerosis and Neuro-intractable Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanzhe","family":"Li","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyo","family":"Yoshino","sequence":"first","affiliation":[{"name":"Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Mori","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayami","family":"Okuzumi","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Yamaguchi","sequence":"first","affiliation":[{"name":"Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risa","family":"Nonaka","sequence":"first","affiliation":[{"name":"Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan"},{"name":"Department of Diagnosis, Prevention and Treatment of Dementia, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nana","family":"Izawa","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei-ichi","family":"Ishikawa","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan"},{"name":"Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidemoto","family":"Saiki","sequence":"first","affiliation":[{"name":"Department of Neurology, Tazuke Kofukai Medical Research Institute and Kitano Hospital, Osaka 530-8480, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayo","family":"Morita","sequence":"first","affiliation":[{"name":"Department of Neurology, Jikei University Katsushika Medical Center, Tokyo 125-8506, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Hasegawa","sequence":"first","affiliation":[{"name":"Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuko","family":"Hasegawa","sequence":"first","affiliation":[{"name":"Department of Neurology, NHO Sagamihara National Hospital, Kanagawa 252-0392, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montasir","family":"Elahi","sequence":"first","affiliation":[{"name":"Department of Diagnosis, Prevention and Treatment of Dementia, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Funayama","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan"},{"name":"Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan"},{"name":"Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Okano","sequence":"first","affiliation":[{"name":"Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wado","family":"Akamatsu","sequence":"first","affiliation":[{"name":"Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzuru","family":"Imai","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan"},{"name":"Department of Research for Parkinson\u2019s Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobutaka","family":"Hattori","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan"},{"name":"Department of Neurodegenerative and Demented Disorders, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan"},{"name":"Department of Treatment and Research in Multiple Sclerosis and Neuro-intractable Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan"},{"name":"Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan"},{"name":"Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,10,10]]},"reference":[{"key":"2020061110243530300_ref1","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1136\/jnnp.51.6.745","article-title":"The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson\u2019s disease","volume":"51","author":"Gibb","year":"1988","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"2020061110243530300_ref2","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nrneurol.2013.275","article-title":"Extracellular \u03b1-synuclein-a novel and crucial factor in Lewy body diseases","volume":"10","author":"Lee","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"2020061110243530300_ref3","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.arr.2017.12.007","article-title":"The genetics of Parkinson disease","volume":"42","author":"Deng","year":"2018","journal-title":"Ageing Res. Rev."},{"key":"2020061110243530300_ref4","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1073\/pnas.1520335113","article-title":"\u03b1-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models","volume":"113","author":"Mazzulli","year":"2016","journal-title":"Proc. Natl Acad. Sci. U. S. A."},{"key":"2020061110243530300_ref5","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3389\/fnagi.2018.00109","article-title":"Cellular and molecular basis of neurodegeneration in Parkinson disease","volume":"10","author":"Zeng","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"2020061110243530300_ref6","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1002\/mds.27193","article-title":"Neuropathology of genetic synucleinopathies with parkinsonism: review of the literature","volume":"32","author":"Schneider","year":"2017","journal-title":"Mov. Disord."},{"key":"2020061110243530300_ref7","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/S1474-4422(14)70266-2","article-title":"CHCHD2 mutations in autosomal dominant late-onset Parkinson\u2019s disease: a genome-wide linkage and sequencing study","volume":"14","author":"Funayama","year":"2015","journal-title":"Lancet Neurol."},{"key":"2020061110243530300_ref8","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.parkreldis.2016.10.018","article-title":"A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson\u2019s disease","volume":"34","author":"Ikeda","year":"2017","journal-title":"Parkinsonism Relat. Disord."},{"key":"2020061110243530300_ref9","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.parkreldis.2017.12.005","article-title":"A new CHCHD2 mutation identified in a southern Italy patient with multiple system atrophy","volume":"47","author":"Nicoletti","year":"2018","journal-title":"Parkinsonism Relat. Disord."},{"key":"2020061110243530300_ref10","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.parkreldis.2016.05.032","article-title":"Mutational scanning of the CHCHD2 gene in Han Chinese patients with Parkinson's disease and meta-analysis of the literature","volume":"29","author":"Yang","year":"2016","journal-title":"Parkinsonism Relat. Disord."},{"key":"2020061110243530300_ref11","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1212\/WNL.0000000000002170","article-title":"Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders","volume":"85","author":"Ogaki","year":"2015","journal-title":"Neurology"},{"key":"2020061110243530300_ref12","doi-asserted-by":"crossref","first-page":"181 e181","DOI":"10.1016\/j.neurobiolaging.2018.02.007","article-title":"Mutation analysis of CHCHD2 and CHCHD10 in Italian patients with mitochondrial myopathy","volume":"66","author":"Rubino","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"2020061110243530300_ref13","doi-asserted-by":"crossref","first-page":"218 e219","DOI":"10.1016\/j.neurobiolaging.2016.10.001","article-title":"Mutation analysis of CHCHD2 gene in Chinese Han familial essential tremor patients and familial Parkinson's disease patients","volume":"49","author":"Gao","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"2020061110243530300_ref14","doi-asserted-by":"crossref","first-page":"169 e165","DOI":"10.1016\/j.neurobiolaging.2016.10.022","article-title":"Analysis of CHCHD2 gene in familial Parkinson\u2019s disease from Calabria","volume":"50","author":"Gagliardi","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"2020061110243530300_ref15","doi-asserted-by":"crossref","first-page":"169 e161","DOI":"10.1016\/j.neurobiolaging.2016.10.019","article-title":"Genetic analysis of CHCHD2 in a southern Spanish population","volume":"50","author":"Tejera-Parrado","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"2020061110243530300_ref16","doi-asserted-by":"crossref","first-page":"217 e217","DOI":"10.1016\/j.neurobiolaging.2015.10.038","article-title":"Mutation analysis of CHCHD2 in Canadian patients with familial Parkinson\u2019s disease","volume":"38","author":"Zhang","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"2020061110243530300_ref17","doi-asserted-by":"crossref","first-page":"3117 e3117","DOI":"10.1016\/j.neurobiolaging.2015.08.010","article-title":"Mutation analysis of CHCHD2 gene in Chinese familial Parkinson\u2019s disease","volume":"36","author":"Liu","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"2020061110243530300_ref18","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/S1474-4422(15)00094-0","article-title":"CHCHD2 and Parkinson\u2019s disease","volume":"14","author":"Jansen","year":"2015","journal-title":"Lancet Neurol."},{"key":"2020061110243530300_ref19","doi-asserted-by":"crossref","first-page":"15500","DOI":"10.1038\/ncomms15500","article-title":"Loss of Parkinson's disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c","volume":"8","author":"Meng","year":"2017","journal-title":"Nat. Commun."},{"key":"2020061110243530300_ref20","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1093\/nar\/gks1454","article-title":"Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2","volume":"41","author":"Aras","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"2020061110243530300_ref21","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1000590","article-title":"A computational screen for regulators of oxidative phosphorylation implicates SLIRP in mitochondrial RNA homeostasis","volume":"5","author":"Baughman","year":"2009","journal-title":"PLoS Genet."},{"key":"2020061110243530300_ref22","doi-asserted-by":"crossref","DOI":"10.3390\/ijms20040908","article-title":"Twin CHCH proteins, CHCHD2, and CHCHD10: key molecules of Parkinson\u2019s disease, amyotrophic lateral sclerosis, and frontotemporal dementia","volume":"20","author":"Imai","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"2020061110243530300_ref23","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1093\/brain\/awu138","article-title":"A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement","volume":"137","author":"Bannwarth","year":"2014","journal-title":"Brain"},{"key":"2020061110243530300_ref24","doi-asserted-by":"crossref","first-page":"58","DOI":"10.15252\/emmm.201505496","article-title":"CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis","volume":"8","author":"Genin","year":"2016","journal-title":"EMBO Mol. 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