中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (1): 196-204.doi: 10.4103/1673-5374.378010

• 原著:神经损伤修复保护与再生 • 上一篇    下一篇

帕金森病CHCHD2 Thr61Ile突变可损害F1F0-ATP酶的组装

  

  • 出版日期:2024-01-15 发布日期:2023-08-02
  • 基金资助:
    国家自然科学基金青年计划项目（81901282）；国家自然科学基金项目（81401416，81870992，81870856）；广东省基础与应用基础研究基金科学基金项目（2019A1515011189）；中央指导地方科技发展项目（ZYYD2022C17）；广州市卫生健康委员会重点项目（2019-ZD-09）；广州市科技规划项目（202102020029，202102010010）

CHCHD2 Thr61Ile mutation impairs F1F0-ATPase assembly in in vitro and in vivo models of Parkinson’s disease

Xiang Chen1, #, Yuwan Lin1, #, Zhiling Zhang1, Yuting Tang1, Panghai Ye1, Wei Dai1, Wenlong Zhang1, Hanqun Liu1, Guoyou Peng1, Shuxuan Huang2, Jiewen Qiu1, Wenyuan Guo1, Xiaoqin Zhu3, Zhuohua Wu1, Yaoyun Kuang1, *, Pingyi Xu1, *, Miaomiao Zhou1, 4, *   

  1. 1Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China; 2Department of Neurology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region, China; 3School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong Province, China; 4Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • Online:2024-01-15 Published:2023-08-02
  • Contact: Miaomiao Zhou, MD, PhD, zhouzhou8601@126.com; Pingyi Xu, MD, PhD, pingyixu@sina.com; Yaoyun Kuang, MD, PhD, Kuangyaoyun@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China (Youth Program), No. 81901282 (to XC); the National Natural Science Foundation of China, Nos. 81401416 (to PX), 81870992 (to PX), 81870856 (to XC and MZ); Guangdong Basic and Applied Basic Research Foundation the Science Foundation, No. 2019A1515011189 (to XC); Central Government Guiding Local Science and Technology Development Projects, No. ZYYD2022C17 (to PX); Key Project of Guangzhou Health Commission, No. 2019-ZD-09 (to PX); and Science and Technology Planning Project of Guangzhou, Nos. 202102020029 (to XC), 202102010010 (to PX).

PDF

114

摘要：

线粒体功能障碍是帕金森病的重要病理变化之一，且CHCHD2 Th61Ile （T61I）突变可导致帕金森病。F1F0-ATP酶可参与细胞ATP的合成，并在线粒体能量代谢中占据重要地位。然而，CHCHD2或CHCHD2 T61I突变是否可通过调控F1F0-ATPase活性而影响线粒体功能功能仍不清楚。为此，实验构建了野生型CHCHD2和CHCHD2 T61I过表达SHSY5Y细胞株，并以MPP+诱导帕金森病细胞模型。可见CHCHD2对MPP+诱导的线粒体功能障碍具有保护作用。在正常条件下，野生型CHCHD2过表达可促进F1F0-ATP酶的组装，而T61I CHCHD2突变似乎丧失了调节F1F0-ATPase组装的功能。此外，质谱分析和免疫共沉淀结果表明，CHCHD2与F1F0-ATP酶存在相互作用。然后在转染AAV-CHHD2 T61I后3周时腹腔注射MPTP诱导慢性PD小鼠模型，发现小鼠的行为障碍和多巴胺能神经退行性变进一步恶化。因此说明野生型CHCHD2可通过维持F1F0-ATP酶结构和功能的稳定性来减缓帕金森病线粒体功能障碍。

https://orcid.org/0000-0003-4426-1758 (Miaomiao Zhou); https://orcid.org/0000-0001-8716-5892 (Pingyi Xu); https://orcid.org/0000-0002-7635-8442 (Yaoyun Kuang)

关键词: 帕金森病, CHCHD2, T61I突变, 线粒体功能障碍, ATP合成酶, F1F0-ATP酶, 寡霉素敏感相关蛋白, 酪氨酸羟化酶, 多巴胺能神经元, 神经退行性变

Abstract: Mitochondrial dysfunction is a significant pathological alteration that occurs in Parkinson’s disease (PD), and the Thr61Ile (T61I) mutation in coiled-coil helix coiled-coil helix domain containing 2 (CHCHD2), a crucial mitochondrial protein, has been reported to cause Parkinson’s disease. F1F0-ATPase participates in the synthesis of cellular adenosine triphosphate (ATP) and plays a central role in mitochondrial energy metabolism. However, the specific roles of wild-type (WT) CHCHD2 and T61I-mutant CHCHD2 in regulating F1F0-ATPase activity in Parkinson’s disease, as well as whether CHCHD2 or CHCHD2 T61I affects mitochondrial function through regulating F1F0-ATPase activity, remain unclear. Therefore, in this study, we expressed WT CHCHD2 and T61I-mutant CHCHD2 in an MPP+-induced SH-SY5Y cell model of PD. We found that CHCHD2 protected mitochondria from developing MPP+-induced dysfunction. Under normal conditions, overexpression of WT CHCHD2 promoted F1F0-ATPase assembly, while T61I-mutant CHCHD2 appeared to have lost the ability to regulate F1F0-ATPase assembly. In addition, mass spectrometry and immunoprecipitation showed that there was an interaction between CHCHD2 and F1F0-ATPase. Three weeks after transfection with AAV-CHCHD2 T61I, we intraperitoneally injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into mice to establish an animal model of chronic Parkinson’s disease and found that exogenous expression of the mutant protein worsened the behavioral deficits and dopaminergic neurodegeneration seen in this model. These findings suggest that WT CHCHD2 can alleviate mitochondrial dysfunction in PD by maintaining F1F0-ATPase structure and function.

Key words: ATP synthase (F1F0-ATPase), coiled-coil helix coiled-coil helix domain containing 2, dopaminergic neuron, mitochondrial dysfunction, neurodegeneration, oligomycin sensitivity-conferring protein, Parkinson’s disease, T61I mutation, tyrosine hydroxylase