Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, 467-8603, Japan.
Nat Commun. 2018 Jul 10;9(1):2668. doi: 10.1038/s41467-018-05127-2.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder. Despite its severity, there are no effective treatments because of the complexity of its pathogenesis. As one of the underlying mechanisms of Cu, Zn superoxide dismutase (SOD1) gene mutation-induced ALS, SOD1 mutants (SOD1) commonly interact with an endoplasmic reticulum-resident membrane protein Derlin-1, triggering motoneuron death. However, the importance of SOD1-Derlin-1 interaction in in vitro human model and in vivo mouse model remains to be elucidated. Here, we identify small-molecular-weight compounds that inhibit the SOD1-Derlin-1 interaction by screening approximately 160,000 compounds. The inhibitor prevents 122 types of SOD1 from interacting with Derlin-1, and significantly ameliorates the ALS pathology both in motoneurons derived from patient induced pluripotent stem cells and in model mice. Our data suggest that the SOD1-Derlin-1 interaction contributes to the pathogenesis of ALS and is a promising drug target for ALS treatment.
肌萎缩侧索硬化症（ALS）是一种毁灭性的神经退行性疾病。尽管其严重程度很高，但由于其发病机制复杂，目前尚无有效的治疗方法。作为铜锌超氧化物歧化酶（SOD1）基因突变诱导的 ALS 的潜在机制之一，SOD1 突变体（SOD1）通常与内质网驻留膜蛋白 Derlin-1 相互作用，引发运动神经元死亡。然而，SOD1-Derlin-1 相互作用在体外人类模型和体内小鼠模型中的重要性仍有待阐明。在这里，我们通过筛选大约 160,000 种化合物来鉴定出抑制 SOD1-Derlin-1 相互作用的小分子化合物。该抑制剂可防止 122 种类型的 SOD1 与 Derlin-1 相互作用，并显著改善源自患者诱导多能干细胞的运动神经元和模型小鼠中的 ALS 病理学。我们的数据表明，SOD1-Derlin-1 相互作用导致 ALS 的发病机制，并为 ALS 治疗提供了一个有前途的药物靶点。
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