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A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

Author

Listed:
  • Takenari Yamashita

    (CREST, Japan Science and Technology Agency, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
    University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
    Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan)

  • Takuto Hideyama

    (CREST, Japan Science and Technology Agency, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
    University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan)

  • Kosuke Hachiga

    (University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan)

  • Sayaka Teramoto

    (CREST, Japan Science and Technology Agency, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
    University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
    Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan)

  • Jiro Takano

    (Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan)

  • Nobuhisa Iwata

    (Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan
    Laboratory of Molecular Biology and Biotechnology, Graduate School of Biomedical Sciences Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan)

  • Takaomi C. Saido

    (Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan)

  • Shin Kwak

    (CREST, Japan Science and Technology Agency, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
    University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
    Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
    Clinical Research Center for Medicine, International University of Health and Welfare, 6-1-14 Konodai, Ichikawa, Chiba 272-0827, Japan)

Abstract

Both mislocalization of TDP-43 and downregulation of RNA-editing enzyme ADAR2 co-localize in the motor neurons of amyotrophic lateral sclerosis patients, but how they are linked is not clear. Here we demonstrate that activation of calpain, a Ca2+-dependent cysteine protease, by upregulation of Ca2+-permeable AMPA receptors generates carboxy-terminal-cleaved TDP-43 fragments and causes mislocalization of TDP-43 in the motor neurons expressing glutamine/arginine site-unedited GluA2 of conditional ADAR2 knockout (AR2) mice that mimic the amyotrophic lateral sclerosis pathology. These abnormalities are inhibited in the AR2res mice that express Ca2+-impermeable AMPA receptors in the absence of ADAR2 and in the calpastatin transgenic mice, but are exaggerated in the calpastatin knockout mice. Additional demonstration of calpain-dependent TDP43 fragments in the spinal cord and brain of amyotrophic lateral sclerosis patients, and high vulnerability of amyotrophic lateral sclerosis-linked mutant TDP43 to cleavage by calpain support the crucial role of the calpain-dependent cleavage of TDP43 in the amyotrophic lateral sclerosis pathology.

Suggested Citation

  • Takenari Yamashita & Takuto Hideyama & Kosuke Hachiga & Sayaka Teramoto & Jiro Takano & Nobuhisa Iwata & Takaomi C. Saido & Shin Kwak, 2012. "A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology," Nature Communications, Nature, vol. 3(1), pages 1-13, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms2303
    DOI: 10.1038/ncomms2303
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