Mutations in CHCHD2 cause α-synuclein aggregation

Aya Ikeda, Kenya Nishioka, Hongrui Meng, Masashi Takanashi, Iwao Hasegawa, Tsuyoshi Inoshita, Kahori Shiba-Fukushima, Yuanzhe Li, Hiroyo Yoshino, Akio Mori, Ayami Okuzumi, Akihiro Yamaguchi, Risa Nonaka, Nana Izawa, Kei Ichi Ishikawa, Hidemoto Saiki, Masayo Morita, Masato Hasegawa, Kazuko Hasegawa, Montasir ElahiManabu Funayama, Hideyuki Okano, Wado Akamatsu, Yuzuru Imai, Nobutaka Hattori

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


Mutations in CHCHD2 are linked to a familial, autosomal dominant form of Parkinson's disease (PD). The gene product may regulate mitochondrial respiratory function. However, whether mitochondrial dysfunction induced by CHCHD2 mutations further yields α-synuclein pathology is unclear. Here, we provide compelling genetic evidence that mitochondrial dysfunction induced by PD-linked CHCHD2 T61I mutation promotes α-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 α-synuclein aggregates, the extent of which was comparable to that of a case with α-synuclein (SNCA) duplication, was observed in CHCHD2 T61I brain tissue. The prion-like activity and morphology of α-synuclein fibrils from the CHCHD2 T61I brain tissue were similar to those of fibrils from SNCA duplication and sporadic PD brain tissues. α-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 α-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 α-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 α-synuclein stability in the etiology of PD.

Original languageEnglish
Pages (from-to)3895-3911
Number of pages17
JournalHuman molecular genetics
Issue number23
Publication statusPublished - 2019 Dec 1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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