SOD1-Derlin-1結合を標的としたALS治療薬の基盤開発

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 一條 秀憲, 東京大学教授 新井 洋由, 東京大学教授 村田 茂穂, 東京大学教授 富田 泰輔, 東京大学准教授 千原 崇裕University of Tokyo(東京大学

A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model

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 (SOD1mut) 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 SOD1mut 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