2. Academic Validation
  3. A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model

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

  • Nat Commun. 2018 Jul 10;9(1):2668. doi: 10.1038/s41467-018-05127-2.
Naomi Tsuburaya 1,  Kengo Homma 1,  Tsunehiko Higuchi 2,  Andrii Balia 3,  Hiroyuki Yamakoshi 2,  Norio Shibata 3,  Seiichi Nakamura 2,  Hidehiko Nakagawa 2,  Shin-Ichi Ikeda 2,  Naoki Umezawa 2,  Nobuki Kato 2,  Satoshi Yokoshima 4,  Masatoshi Shibuya 4,  Manabu Shimonishi 5,  Hirotatsu Kojima 6,  Takayoshi Okabe 6,  Tetsuo Nagano 6,  Isao Naguro 1,  Keiko Imamura 7 8 9,  Haruhisa Inoue 7 8 9,  Takao Fujisawa 1,  Hidenori Ichijo 10 11
Affiliations

Affiliations

  • 1 Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
  • 2 Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, 467-8603, Japan.
  • 3 Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya, 466-8555, Japan.
  • 4 Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
  • 5 GCOE Program, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
  • 6 Drug Discovery Initiative (DDI), The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
  • 7 Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
  • 8 iPSC-based Drug Discovery and Development Team, RIKEN BioResource Center, Kyoto, 606-8507, Japan.
  • 9 Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (RIKEN AIP), Kyoto, 606-8507, Japan.
  • 10 Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. [email protected].
  • 11 Drug Discovery Initiative (DDI), The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. [email protected].
PMID: 29991716 DOI: 10.1038/s41467-018-05127-2
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.

Figures
Products