期刊
HUMAN MOLECULAR GENETICS
卷 28, 期 23, 页码 3895-3911出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddz241
关键词
-
资金
- Takeda Science Foundation
- Naito Foundation
- Otsuka Pharmaceutical
- Biogen Japan Ltd
- Japan Society for the Promotion of Science in Japan
- Research Center Network for Realization Research Centers/Projects of Regenerative Medicine (the Program for Intractable Disease Research Utilizing Disease-specific iPS Cells and the Acceleration Program for Intractable Diseases Research Utilizing Disease-s [JP17bm0804003]
- Practical Research Project for Rare/Intractable Diseases from AMED [JP17ek0109244]
- Research Project for Practical Applications of Regenerative Medicine from AMED [JP16bk0104033]
- Advanced Genome Research and Bioinformatics Study to Facilitate Medical Innovation (GRIFIN) from AMED [JP19km0405206s0104]
- [2586076]
- [18K15463]
- [23129506]
- [25129707]
- [25461291]
- [15KK0354]
- [16K09676]
- [17H04049]
- [18K15465]
- [18H04043]
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 alpha-synuclein pathology is unclear. Here, we provide compelling genetic evidence that mitochondrial dysfunction induced by PD-linked CHCHD2 T61I mutation promotes a-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 alpha-synuclein aggregates, the extent of which was comparable to that of a case with alpha-synuclein (SNCA) duplication, was observed in CHCHD2 T61I brain tissue. The prion-like activity and morphology of alpha-synuclein fibrils from the CHCHD2 T61I brain tissue were similar to those of fibrils from SNCA duplication and sporadic PD brain tissues. a-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 alpha-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 alpha-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 alpha-synuclein stability in the etiology of PD.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据