Chen Yanbo, Deng Jianwen, Wang Peng, Yang Mengxue, Chen Xiaoping, Zhu Li, Liu Jianghong, Lu Bingwei, Shen Yan, Fushimi Kazuo, Xu Qi, Wu Jane Y
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Science, Beijing, China.
Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Superior, Chicago, IL, USA.
Hum Mol Genet. 2016 Dec 1;25(23):5059-5068. doi: 10.1093/hmg/ddw310.
Dysregulation of Fused in Sarcoma (FUS) gene expression is associated with fronto-temporal lobar degeneration (FTLD), and missense mutations in the FUS gene have been identified in patients affected by amyotrophic lateral sclerosis (ALS). However, molecular and cellular defects underlying FUS proteinopathy remain to be elucidated. Here, we examined whether genes important for mitochondrial quality control play a role in FUS proteinopathy. In our genetic screening, Pink1 and Park genes were identified as modifiers of neurodegeneration phenotypes induced by wild type (Wt) or ALS-associated P525L-mutant human FUS. Down-regulating expression of either Pink1 or Parkin genes ameliorated FUS-induced neurodegeneration phenotypes. The protein levels of PINK1 and Parkin were elevated in cells overexpressing FUS. Remarkably, ubiquitinylation of Miro1 protein, a downstream target of the E3 ligase activity of Parkin, was also increased in cells overexpressing FUS protein. In fly motor neurons expressing FUS, both motility and processivity of mitochondrial axonal transport were reduced by expression of either Wt- or P525L-mutant FUS. Finally, down-regulating PINK1 or Parkin partially rescued the locomotive defects and enhanced the survival rate in transgenic flies expressing FUS. Our data indicate that PINK1 and Parkin play an important role in FUS-induced neurodegeneration. This study has uncovered a previously unknown link between FUS proteinopathy and PINK1/Parkin genes, providing new insights into the pathogenesis of FUS proteinopathy.
肉瘤融合蛋白（FUS）基因表达失调与额颞叶痴呆（FTLD）相关，并且在肌萎缩侧索硬化症（ALS）患者中已鉴定出FUS基因的错义突变。然而，FUS蛋白病潜在的分子和细胞缺陷仍有待阐明。在此，我们研究了对线粒体质量控制重要的基因是否在FUS蛋白病中起作用。在我们的基因筛选中，Pink1和Park基因被鉴定为野生型（Wt）或ALS相关的P525L突变型人类FUS诱导的神经退行性表型的修饰因子。下调Pink1或Parkin基因的表达可改善FUS诱导的神经退行性表型。在过表达FUS的细胞中，PINK1和Parkin的蛋白水平升高。值得注意的是，在过表达FUS蛋白的细胞中，Parkin E3连接酶活性的下游靶点Miro1蛋白的泛素化也增加。在表达FUS的果蝇运动神经元中，野生型或P525L突变型FUS的表达均降低了线粒体轴突运输的运动性和持续性。最后，下调PINK1或Parkin可部分挽救转基因果蝇表达FUS时的运动缺陷并提高存活率。我们的数据表明，PINK1和Parkin在FUS诱导的神经退行性变中起重要作用。这项研究揭示了FUS蛋白病与PINK1/Parkin基因之间以前未知的联系，为FUS蛋白病的发病机制提供了新的见解。
