Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan, South Korea.
Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, South Korea.
Insect Mol Biol. 2020 Feb;29(1):56-65. doi: 10.1111/imb.12608. Epub 2019 Jul 12.
Fused in sarcoma (FUS) is a DNA/RNA-binding protein associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. The exact molecular mechanisms by which FUS results in neurotoxicity have not yet been fully elucidated. Here, we found that parkin is a genetic suppressor of defective phenotypes induced by exogenous human wild type FUS in Drosophila. Although parkin overexpression did not modulate the FUS protein expression level, the locomotive defects in FUS-expressing larvae and adult flies were rescued by parkin expression. We found that FUS expression in muscle tissues resulted in a reduction of the levels and assembly of mitochondrial complex I and III subunits, as well as decreased ATP. Remarkably, expression of parkin suppressed these mitochondrial dysfunctions. Our results indicate parkin as a neuroprotective regulator of FUS-induced proteinopathy by recovering the protein levels of mitochondrial complexes I and III. Our findings on parkin-mediated neuroprotection may expand our understanding of FUS-induced ALS pathogenesis.
融合肉瘤（FUS）是一种与肌萎缩侧索硬化症（ALS）和额颞叶变性相关的 DNA/RNA 结合蛋白。FUS 导致神经毒性的确切分子机制尚未完全阐明。在这里，我们发现 parkin 是果蝇中外源人野生型 FUS 诱导的缺陷表型的遗传抑制剂。尽管 parkin 的过表达不能调节 FUS 蛋白的表达水平，但 parkin 的表达挽救了 FUS 表达的幼虫和成年果蝇的运动缺陷。我们发现，肌肉组织中 FUS 的表达导致线粒体复合物 I 和 III 亚基的水平和组装减少，以及 ATP 减少。值得注意的是，parkin 的表达抑制了这些线粒体功能障碍。我们的结果表明 parkin 作为 FUS 诱导的蛋白病的神经保护调节剂，通过恢复线粒体复合物 I 和 III 的蛋白水平。我们关于 parkin 介导的神经保护的发现可能会扩展我们对 FUS 诱导的 ALS 发病机制的理解。
