Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity.
Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity.
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DOI：
10.1038/ncomms15558
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发表时间：
2017-06-06
影响因子：
16.6
通讯作者：
Kang DE
中科院分区：
文献类型：
--
作者：
Woo JA;Liu T;Trotter C;Fang CC;De Narvaez E;LePochat P;Maslar D;Bukhari A;Zhao X;Deonarine A;Westerheide SD;Kang DE
尽管CHCHD10的多发性突变与家族性和散发性额颞叶痴呆-肌萎缩侧索硬化症(FTD-ALS)疾病有关，但内源性CHCHD10的正常功能及其在FTD/ALS的病理环境(即TDP-43病理)中的作用尚未得到研究。在本研究中，我们利用线虫模型、哺乳动物细胞系、原代神经元和小鼠大脑进行了一系列观察，表明CHCHD10正常情况下对线粒体和突触的完整性以及核TDP-43的保留具有保护作用，而与FTD/ALS相关的突变(R15L和S59L)在线虫遗传互补分析中表现出功能缺失的表型，并在哺乳动物系统中表现出明显的负活动，导致线粒体/突触损伤和细胞质TDP-43积聚。因此，我们的结果提供了CHCHD10相关的线粒体/突触功能障碍和细胞质TDP-43包涵体之间的病理联系。CHCHD10的突变最近被认为与额颞痴呆和肌萎缩侧索硬化症有关。在这里，作者研究了内源性CHCHD10在秀丽线虫、原代神经元和小鼠中的功能，表明它正常地保护线粒体和突触的完整性，并将TDP-43保留在细胞核中。
Although multiple CHCHD10 mutations are associated with the spectrum of familial and sporadic frontotemporal dementia–amyotrophic lateral sclerosis (FTD–ALS) diseases, neither the normal function of endogenous CHCHD10 nor its role in the pathological milieu (that is, TDP-43 pathology) of FTD/ALS have been investigated. In this study, we made a series of observations utilizing Caenorhabditis elegans models, mammalian cell lines, primary neurons and mouse brains, demonstrating that CHCHD10 normally exerts a protective role in mitochondrial and synaptic integrity as well as in the retention of nuclear TDP-43, whereas FTD/ALS-associated mutations (R15L and S59L) exhibit loss of function phenotypes in C. elegans genetic complementation assays and dominant negative activities in mammalian systems, resulting in mitochondrial/synaptic damage and cytoplasmic TDP-43 accumulation. As such, our results provide a pathological link between CHCHD10-associated mitochondrial/synaptic dysfunction and cytoplasmic TDP-43 inclusions. Mutations in CHCHD10 have been recently associated with frontotemporal dementia and amyotrophic lateral sclerosis. Here the authors study the functions of endogenous CHCHD10 in Caenorhabditis elegans, primary neurons, and mouse, and show that it normally protects mitochondria and synaptic integrity, and retains TDP-43 in the nucleus.