Mutations in CHCHD2 cause α-synuclein aggregation

Author:

Ikeda Aya1,Nishioka Kenya1,Meng Hongrui2,Takanashi Masashi1,Hasegawa Iwao3,Inoshita Tsuyoshi4,Shiba-Fukushima Kahori4,Li Yuanzhe1,Yoshino Hiroyo5,Mori Akio1,Okuzumi Ayami1,Yamaguchi Akihiro6,Nonaka Risa67,Izawa Nana1,Ishikawa Kei-ichi16,Saiki Hidemoto8,Morita Masayo9,Hasegawa Masato10,Hasegawa Kazuko11,Elahi Montasir7,Funayama Manabu156,Okano Hideyuki12,Akamatsu Wado6,Imai Yuzuru113,Hattori Nobutaka12456

Affiliation:

1. Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan

2. Department of Neurodegenerative and Demented Disorders, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan

3. University Center of Legal Medicine, Kanagawa Dental University, Kanagawa 238-8580, Japan

4. Department of Treatment and Research in Multiple Sclerosis and Neuro-intractable Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan

5. Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan

6. Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan

7. Department of Diagnosis, Prevention and Treatment of Dementia, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan

8. Department of Neurology, Tazuke Kofukai Medical Research Institute and Kitano Hospital, Osaka 530-8480, Japan

9. Department of Neurology, Jikei University Katsushika Medical Center, Tokyo 125-8506, Japan

10. Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan

11. Department of Neurology, NHO Sagamihara National Hospital, Kanagawa 252-0392, Japan

12. Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan

13. Department of Research for Parkinson’s Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan

Abstract

Abstract 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.

Funder

Scientific Research

Japan Society for the Promotion of Science

Takeda Science Foundation

Naito Foundation

Otsuka Pharmaceutical

Biogen

Research Center Network for Realization Research Centers/Projects of Regenerative Medicine

AMED

Practical Research Project for Rare/Intractable Diseases

Advanced Genome Research and Bioinformatics Study to Facilitate Medical Innovation

Research Project for Practical Applications of Regenerative Medicine

Publisher

Oxford University Press (OUP)

Subject

Genetics(clinical),Genetics,Molecular Biology,General Medicine

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