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

Naomi Tsuburaya, Kengo Homma, Tsunehiko Higuchi, Andrii Balia, Hiroyuki Yamakoshi, Norio Shibata, Seiichi Nakamura, Hidehiko Nakagawa, Shin-ichi Ikeda, Naoki Umezawa, Nobuki Kato, Satoshi Yokoshima, Masatoshi Shibuya, Manabu Shimonishi, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Isao Naguro, Keiko Imamura, Haruhisa Inoue, Takao Fujisawa and Hidenori Ichijo ()
Additional contact information
Naomi Tsuburaya: The University of Tokyo
Kengo Homma: The University of Tokyo
Tsunehiko Higuchi: Nagoya City University
Andrii Balia: Nagoya Institute of Technology
Hiroyuki Yamakoshi: Nagoya City University
Norio Shibata: Nagoya Institute of Technology
Seiichi Nakamura: Nagoya City University
Hidehiko Nakagawa: Nagoya City University
Shin-ichi Ikeda: Nagoya City University
Naoki Umezawa: Nagoya City University
Nobuki Kato: Nagoya City University
Satoshi Yokoshima: Nagoya University
Masatoshi Shibuya: Nagoya University
Manabu Shimonishi: The University of Tokyo
Hirotatsu Kojima: The University of Tokyo
Takayoshi Okabe: The University of Tokyo
Tetsuo Nagano: The University of Tokyo
Isao Naguro: The University of Tokyo
Keiko Imamura: Kyoto University
Haruhisa Inoue: Kyoto University
Takao Fujisawa: The University of Tokyo
Hidenori Ichijo: The University of Tokyo

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05127-2

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