A mutant <i>MATR3</i> mouse model to explain multisystem proteinopathy

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  • Xiao Zhang
    Department of Neurology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan
  • Satoshi Yamashita
    Department of Neurology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan
  • Kentaro Hara
    Department of Neurology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan
  • Tsukasa Doki
    Department of Neurology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan
  • Nozomu Tawara
    Department of Neurology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan
  • Tokunori Ikeda
    Department of Neurology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan
  • Yohei Misumi
    Department of Neurology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan
  • Ziwei Zhang
    Department of Neurology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan
  • Yoshimasa Matsuo
    Department of Neurology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan
  • Makiko Nagai
    Department of Neurology Kitasato University School of Medicine Sagamihara Japan
  • Takashi Kurashige
    Department of Neurology National Hospital Organization Kure Medical Centre Kure Hiroshima Japan
  • Hirofumi Maruyama
    Department of Clinical Neuroscience and Therapeutics Hiroshima University Graduate School of Biomedical and Health Sciences Hiroshima Japan
  • Yukio Ando
    Department of Neurology, Graduate School of Medical Sciences Kumamoto University Kumamoto Japan

説明

<jats:title>Abstract</jats:title><jats:p>Mutations in the <jats:italic>Matrin 3</jats:italic> (<jats:italic>MATR3</jats:italic>) gene have been identified as a cause of amyotrophic lateral sclerosis (ALS) or vocal cord and pharyngeal weakness with distal myopathy (VCPDM). This study investigated the mechanism by which mutant <jats:italic>MATR3</jats:italic> causes multisystem proteinopathy (MSP) including ALS and VCPDM. We first analyzed the muscle pathology of C57BL/6 mice injected with adeno‐associated viruses expressing human WT or mutant (S85C) <jats:italic>MATR3</jats:italic>. We next generated transgenic mice that overexpress mutant (S85C) <jats:italic>MATR3</jats:italic>, driven by the CMV early enhancer/chicken β‐actin promoter, and evaluated their clinicopathological features. Intramuscular injection of viruses expressing WT and mutant <jats:italic>MATR3</jats:italic> induced similar myogenic changes, including smaller myofibers with internal nuclei, and upregulated p62 and LC3‐II. Mutant <jats:italic>MATR3</jats:italic> transgenic mice showed decreased body weight and lower motor activity. Muscle histology demonstrated myopathic changes including fiber‐size variation, internal nuclei and rimmed vacuoles. Spinal cord histology showed a reduced number of motor neurons, and activation of microglia and astrocytes. Comprehensive proteomic analyses of muscle demonstrated upregulation of proteins related to chaperones, stress response, protein degradation, and nuclear function. Overexpression of WT and mutant <jats:italic>MATR3</jats:italic> similarly caused myotoxicity, recapitulating the clinicopathological features of MSP. These models will be helpful for analyzing MSP pathogenesis and for understanding the function of <jats:italic>MATR3</jats:italic>. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</jats:p>

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