State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):E9678-E9686. doi: 10.1073/pnas.1806655115. Epub 2018 Sep 24.
FUS (fused in sarcoma) proteinopathy is a group of neurodegenerative diseases characterized by the formation of inclusion bodies containing the FUS protein, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Previous studies show that mitochondrial damage is an important aspect of FUS proteinopathy. However, the molecular mechanisms by which FUS induces mitochondrial damage remain to be elucidated. Our biochemical and genetic experiments demonstrate that FUS interacts with the catalytic subunit of mitochondrial ATP synthase (ATP5B), disrupts the formation of ATP synthase complexes, and inhibits mitochondrial ATP synthesis. FUS expression activates the mitochondrial unfolded protein response (UPR). Importantly, down-regulating expression of ATP5B or UPR genes in FUS transgenic flies ameliorates neurodegenerative phenotypes. Our data show that mitochondrial impairment is a critical early event in FUS proteinopathy, and provide insights into the pathogenic mechanism of FUS-induced neurodegeneration.
融合基因（FUS）蛋白病是一组以包含 FUS 蛋白的包涵体形成为特征的神经退行性疾病，包括额颞叶痴呆和肌萎缩性侧索硬化症。先前的研究表明，线粒体损伤是 FUS 蛋白病的一个重要方面。然而，FUS 诱导线粒体损伤的分子机制仍有待阐明。我们的生化和遗传实验表明，FUS 与线粒体 ATP 合酶（ATP5B）的催化亚基相互作用，破坏 ATP 合酶复合物的形成，并抑制线粒体 ATP 合成。FUS 表达激活线粒体未折叠蛋白反应（UPR）。重要的是，下调 FUS 转基因果蝇中 ATP5B 或 UPR 基因的表达可改善神经退行性表型。我们的数据表明，线粒体损伤是 FUS 蛋白病的一个关键早期事件，并为 FUS 诱导的神经退行性变的发病机制提供了新的见解。
