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

Author

Listed:
  • 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
    RIKEN BioResource Center
    RIKEN Center for Advanced Intelligence Project (RIKEN AIP))

  • Haruhisa Inoue

    (Kyoto University
    RIKEN BioResource Center
    RIKEN Center for Advanced Intelligence Project (RIKEN AIP))

  • Takao Fujisawa

    (The University of Tokyo)

  • Hidenori Ichijo

    (The University of Tokyo
    The University of Tokyo)

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.

Suggested Citation

  • Naomi Tsuburaya & Kengo Homma & Tsunehiko Higuchi & Andrii Balia & Hiroyuki Yamakoshi & Norio Shibata & Seiichi Nakamura & Hidehiko Nakagawa & Shin-ichi Ikeda & Naoki Umezawa & Nobuki Kato & Satoshi Y, 2018. "A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05127-2
    DOI: 10.1038/s41467-018-05127-2
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