A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement
A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement
复制标题
DOI：
10.1093/brain/awu138
复制
发表时间：
2014-08-01
期刊：
影响因子：
14.5
通讯作者：
Paquis-Flucklinger, Veronique
中科院分区：
文献类型：
--
作者：
Bannwarth, Sylvie;Ait-El-Mkadem, Samira;Paquis-Flucklinger, Veronique
使用全外显子组测序，Bannwarth等人在两个额颞叶痴呆-肌萎缩侧索硬化症（FTD-ALS）家族中鉴定了线粒体基因CHCHD10的错义突变。CHCHD10有助于维持线粒体嵴的形态和线粒体DNA的稳定性。线粒体DNA不稳定性疾病可导致广泛的临床表现，其中肌萎缩侧索硬化样症状和额颞叶痴呆极为罕见。我们报告了一个迟发性表型包括运动神经元病、类似额颞叶痴呆的认知功能减退、小脑性共济失调和肌病的大家族。在所有患者中，肌肉活检显示破碎的红色和细胞色素c氧化酶阴性的纤维与呼吸链缺陷和异常组装的复合物V。在骨骼肌中发现的多个线粒体DNA缺失揭示了线粒体DNA不稳定性障碍。患者成纤维细胞存在呼吸链缺陷、线粒体超微结构改变和线粒体网络断裂。有趣的是，基质靶向的可光活化GFP的表达显示线粒体融合在患者成纤维细胞中不受抑制。使用全外显子组测序，我们确定了CHCHD10基因中编码卷曲螺旋螺旋蛋白的错义突变（c.176C> T; p.Ser59Leu），其功能未知。我们发现，CHCHD10是一个线粒体蛋白位于膜间隙和丰富的嵴连接。CHCHD10突变等位基因在HeLa细胞中的过表达导致线粒体网络的碎片化和超微结构的主要异常，包括嵴的丢失、解体和扩张。在线粒体疾病中观察到的额颞叶痴呆-肌萎缩侧索硬化表型使我们分析了21个经病理证实的额颞叶痴呆-肌萎缩侧索硬化家族的CHCHD10。我们在其中一个家族中发现了相同的错义p.Ser59Leu突变。这项工作开辟了一个新的领域，探讨额颞叶痴呆-肌萎缩侧索硬化症临床谱的发病机制，显示线粒体疾病可能是这些表型的起源。
Using whole-exome sequencing, Bannwarth et al. identify a missense mutation in the mitochondrial gene, CHCHD10, in two families with frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS). CHCHD10 helps to maintain the morphology of mitochondrial cristae and the stability of mitochondrial DNA. Other cases of FTD-ALS may be mitochondrial in origin.Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C > T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.