Department of Biology, University of Dayton, Dayton, OH 45469, USA.
Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, PA, USA.
Neurobiol Dis. 2020 Jul;140:104837. doi: 10.1016/j.nbd.2020.104837. Epub 2020 Mar 19.
Amyotrophic Lateral Sclerosis (ALS), a late-onset neurodegenerative disorder characterized by the loss of motor neurons in the central nervous system, has no known cure to-date. Disease causing mutations in human Fused in Sarcoma (FUS) leads to aggressive and juvenile onset of ALS. FUS is a well-conserved protein across different species, which plays a crucial role in regulating different aspects of RNA metabolism. Targeted misexpression of FUS in Drosophila model recapitulates several interesting phenotypes relevant to ALS including cytoplasmic mislocalization, defects at the neuromuscular junction and motor dysfunction. We screened for the genetic modifiers of human FUS-mediated neurodegenerative phenotype using molecularly defined deficiencies. We identified hippo (hpo), a component of the evolutionarily conserved Hippo growth regulatory pathway, as a genetic modifier of FUS mediated neurodegeneration. Gain-of-function of hpo triggers cell death whereas its loss-of-function promotes cell proliferation. Downregulation of the Hippo signaling pathway, using mutants of Hippo signaling, exhibit rescue of FUS-mediated neurodegeneration in the Drosophila eye, as evident from reduction in the number of TUNEL positive nuclei as well as rescue of axonal targeting from the retina to the brain. The Hippo pathway activates c-Jun amino-terminal (NH) Kinase (JNK) mediated cell death. We found that downregulation of JNK signaling is sufficient to rescue FUS-mediated neurodegeneration in the Drosophila eye. Our study elucidates that Hippo signaling and JNK signaling are activated in response to FUS accumulation to induce neurodegeneration. These studies will shed light on the genetic mechanism involved in neurodegeneration observed in ALS and other associated disorders.
肌萎缩侧索硬化症（ALS）是一种迟发性神经退行性疾病，其特征是中枢神经系统中的运动神经元丧失，目前尚无已知的治愈方法。人类融合肉瘤（FUS）中的致病突变导致 ALS 的侵袭性和青少年发病。FUS 是一种在不同物种中高度保守的蛋白质，在调节 RNA 代谢的不同方面起着至关重要的作用。在果蝇模型中靶向表达 FUS 会重现与 ALS 相关的几种有趣表型，包括细胞质定位异常、神经肌肉接头缺陷和运动功能障碍。我们使用分子定义的缺陷筛选了人类 FUS 介导的神经退行性表型的遗传修饰因子。我们确定 hippo（hpo）是进化上保守的 Hippo 生长调节途径的一个组成部分，是 FUS 介导的神经退行性变的遗传修饰因子。hpo 的功能获得会触发细胞死亡，而其功能丧失则会促进细胞增殖。使用 Hippo 信号突变体下调 Hippo 信号通路，在果蝇眼中表现出对 FUS 介导的神经退行性变的挽救，从 TUNEL 阳性核数的减少以及视网膜到大脑的轴突靶向的挽救可以明显看出。Hippo 途径激活 c-Jun 氨基末端（NH）激酶（JNK）介导的细胞死亡。我们发现下调 JNK 信号足以挽救果蝇眼中的 FUS 介导的神经退行性变。我们的研究表明，Hippo 信号和 JNK 信号在响应 FUS 积累时被激活，以诱导神经退行性变。这些研究将阐明在 ALS 和其他相关疾病中观察到的神经退行性变的遗传机制。
