論文 - 詳細
| RRC ID | 54120 |
|---|---|
| 著者 | Tsuburaya N, Homma K, Higuchi T, Balia A, Yamakoshi H, Shibata N, Nakamura S, Nakagawa H, Ikeda SI, Umezawa N, Kato N, Yokoshima S, Shibuya M, Shimonishi M, Kojima H, Okabe T, Nagano T, Naguro I, Imamura K, Inoue H, Fujisawa T, Ichijo H. |
| タイトル | A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model. |
| ジャーナル | Nat Commun |
| Abstract |
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. |
| 巻・号 | 9(1) |
| ページ | 2668 |
| 公開日 | 2018-7-10 |
| DOI | 10.1038/s41467-018-05127-2 |
| PII | 10.1038/s41467-018-05127-2 |
| PMID | 29991716 |
| PMC | PMC6039432 |
| MeSH | Amyotrophic Lateral Sclerosis / genetics Amyotrophic Lateral Sclerosis / metabolism Amyotrophic Lateral Sclerosis / prevention & control* Animals Brain / drug effects Brain / metabolism Disease Models, Animal* HEK293 Cells Humans Male Membrane Proteins / genetics Membrane Proteins / metabolism* Mice, Inbred C57BL Mice, Transgenic Protein Binding / drug effects Small Molecule Libraries / pharmacology* Spinal Cord / drug effects Spinal Cord / metabolism Superoxide Dismutase-1 / genetics Superoxide Dismutase-1 / metabolism* |
| IF | 12.121 |
| 引用数 | 6 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 9 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | 201B7(HPS0063) HPS0251 HPS0252 HPS0292 |