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Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy

Author

Listed:
  • Madoka Iida

    (Nagoya University Graduate School of Medicine
    Japan Society for the Promotion of Science)

  • Kentaro Sahashi

    (Nagoya University Graduate School of Medicine)

  • Naohide Kondo

    (Nagoya University Graduate School of Medicine)

  • Hideaki Nakatsuji

    (Nagoya University Graduate School of Medicine)

  • Genki Tohnai

    (Nagoya University Graduate School of Medicine)

  • Yutaka Tsutsumi

    (Nagoya University Graduate School of Medicine)

  • Seiya Noda

    (Nagoya University Graduate School of Medicine
    National Hospital Organization Suzuka National Hospital)

  • Ayuka Murakami

    (Nagoya University Graduate School of Medicine
    National Hospital Organization Suzuka National Hospital)

  • Kazunari Onodera

    (Nagoya University Graduate School of Medicine
    Aichi Medical University School of Medicine)

  • Yohei Okada

    (Nagoya University Graduate School of Medicine
    Aichi Medical University School of Medicine
    Keio University School of Medicine)

  • Masahiro Nakatochi

    (Nagoya University Graduate School of Medicine)

  • Yuka Tsukagoshi Okabe

    (Nagoya University Hospital)

  • Shinobu Shimizu

    (Nagoya University Hospital)

  • Masaaki Mizuno

    (Nagoya University Hospital)

  • Hiroaki Adachi

    (University of Occupational and Environmental Health School of Medicine)

  • Hideyuki Okano

    (Keio University School of Medicine)

  • Gen Sobue

    (Nagoya University)

  • Masahisa Katsuno

    (Nagoya University Graduate School of Medicine)

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. Here, we perform a comprehensive analysis of signaling pathways in a mouse model of SBMA (AR-97Q mice) utilizing a phosphoprotein assay. We measure the levels of 17 phosphorylated proteins in spinal cord and skeletal muscle of AR-97Q mice at three stages. The level of phosphorylated Src (p-Src) is markedly increased in the spinal cords and skeletal muscles of AR-97Q mice prior to the onset. Intraperitoneal administration of a Src kinase inhibitor improves the behavioral and histopathological phenotypes of the transgenic mice. We identify p130Cas as an effector molecule of Src and show that the phosphorylated p130Cas is elevated in murine and cellular models of SBMA. These results suggest that Src kinase inhibition is a potential therapy for SBMA.

Suggested Citation

  • Madoka Iida & Kentaro Sahashi & Naohide Kondo & Hideaki Nakatsuji & Genki Tohnai & Yutaka Tsutsumi & Seiya Noda & Ayuka Murakami & Kazunari Onodera & Yohei Okada & Masahiro Nakatochi & Yuka Tsukagoshi, 2019. "Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12282-7
    DOI: 10.1038/s41467-019-12282-7
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