CHCHD10 参与由 CHCHD2 功能丧失突变 p.T61I 引起的帕金森病的发病机制。
CHCHD10 is involved in the development of Parkinson's disease caused by CHCHD2 loss-of-function mutation p.T61I.
机构信息
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
出版信息
Neurobiol Aging. 2019 Mar;75:38-41. doi: 10.1016/j.neurobiolaging.2018.10.020. Epub 2018 Oct 23.
Previously we identified the p.Thr61Ile mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) in a Chinese family with autosomal dominant Parkinson's disease. But the mechanism is still unclear. In this study, we explored the effects of CHCHD2 p.Thr61Ile mutation in cells and its association with coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10). We found that overexpression of Parkinson's disease-associated T61I mutant CHCHD2 did not produce mitochondrial dysfunction. Rather, its protective effect from stress was abrogated. And, the level of the CHCHD2 protein and mRNA in patient fibroblasts was not significantly different from control. In addition, CHCHD2 T61I mutation caused increased interaction with CHCHD10 and reduced CHCHD10 level. The mitochondrial ultrastructural alterations in CHCHD2 T61I mutant patient fibroblasts are similar to that of CHCHD10 mutations. We therefore propose that CHCHD10 is involved in the development of Parkinson's disease caused by CHCHD2 loss-of-function mutation p.T61I.
先前，我们在中国一个常染色体显性遗传帕金森病家族中发现了卷曲螺旋-环-卷曲螺旋-环-卷曲螺旋结构域蛋白 2（CHCHD2）中的 p.Thr61Ile 突变。但是其机制尚不清楚。在本研究中，我们探讨了 CHCHD2 p.Thr61Ile 突变在细胞中的作用及其与卷曲螺旋-环-卷曲螺旋-环-卷曲螺旋结构域蛋白 10（CHCHD10）的关系。我们发现，帕金森病相关的 T61I 突变型 CHCHD2 的过表达不会导致线粒体功能障碍。相反，它对压力的保护作用被削弱。而且，患者成纤维细胞中 CHCHD2 蛋白和 mRNA 的水平与对照组无显著差异。此外，CHCHD2 T61I 突变导致与 CHCHD10 的相互作用增加，而 CHCHD10 水平降低。CHCHD2 T61I 突变患者成纤维细胞中线粒体超微结构的改变与 CHCHD10 突变相似。因此，我们提出 CHCHD10 参与了由 CHCHD2 功能丧失性突变 p.T61I 引起的帕金森病的发生。
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