Transglutaminase 2 accelerates neuroinflammation in amyotrophic lateral sclerosis through interaction with misfolded superoxide dismutase 1

Authors

  • Miki Oono,

    1. Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Shiga, Japan
    2. Department of Neurology, Kyoto University Graduate school of Medicine, Kyoto, Japan
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    • These authors contributed equally to this work.
  • Ayako Okado-Matsumoto,

    1. System Glycobiology Research Group, RIKEN, Wako, Saitama, Japan
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    • These authors contributed equally to this work.
  • Akemi Shodai,

    1. Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Shiga, Japan
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  • Akemi Ido,

    1. Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Shiga, Japan
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  • Yasuyuki Ohta,

    1. Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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  • Koji Abe,

    1. Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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  • Takashi Ayaki,

    1. Department of Neurology, Kyoto University Graduate school of Medicine, Kyoto, Japan
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  • Hidefumi Ito,

    1. Department of Neurology, Wakayama Medical University, Graduate School of Medicine, Wakayama, Japan
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  • Ryosuke Takahashi,

    1. Department of Neurology, Kyoto University Graduate school of Medicine, Kyoto, Japan
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  • Naoyuki Taniguchi,

    Corresponding author
    1. System Glycobiology Research Group, RIKEN, Wako, Saitama, Japan
    • Address correspondence and reprint requests to Makoto Urushitani, Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta-Tsukinowa-cho, Otsu, Shiga 520-2192, Japan. E-mail: uru@belle-shiga-med.ac.jp or Naoyuki Taniguchi, System Glycobiology Research Group, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. E-mail: tani52@wd5.so-net.ne.jp

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  • Makoto Urushitani

    Corresponding author
    1. Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Shiga, Japan
    • Address correspondence and reprint requests to Makoto Urushitani, Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta-Tsukinowa-cho, Otsu, Shiga 520-2192, Japan. E-mail: uru@belle-shiga-med.ac.jp or Naoyuki Taniguchi, System Glycobiology Research Group, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. E-mail: tani52@wd5.so-net.ne.jp

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Abstract

Although the aberrant assembly of mutant superoxide dismutase 1 (mSOD1) is implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS), the molecular basis of superoxide dismutase 1 (SOD1) oligomerization remains undetermined. We investigated the roles of transglutaminase 2 (TG2), an endogenous cross-linker in mSOD1-linked ALS. TG2 interacted preferentially with mSOD1 and promoted its oligomerization in transfected cells. Purified TG2 directly oligomerized recombinant mutant SOD1 and the apo-form of the wild-type SOD1 proteins in a calcium-dependent manner, indicating that misfolded SOD1 is a substrate of TG2. Moreover, the non-cell-autonomous effect of extracellular TG2 on the neuroinflammation was suggested, since the TG2-mediated soluble SOD1 oligomers induced tumor necrosis factor-α, interleukin-1β, and nitric oxide in microglial BV2 cells. TG2 was up-regulated in the spinal cord of pre-symptomatic G93A SOD1 transgenic mice and in the hypoglossal nuclei of mice suffering nerve ligation. Furthermore, inhibition of spinal TG2 by cystamine significantly delayed the progression and reduced SOD1 oligomers and microglial activation. These results indicate a novel role of TG2 in SOD1 oligomer-mediated neuroinflammation, as well as in the involvement in the intracellular aggregation of misfolded SOD1 in ALS.

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A new role of transglutaminase 2 (TG2) in misfolded SOD1-linked neuroinflammation has been clarified. TG2 recognized and oligomerized only misfolded forms of SOD1, which robustly activated microglia, and induce the expression of proinflammatory molecules such as iNOS, IL-1β, and TNF-α. The inhibition of spinal cord TG2 of mutant SOD1 transgenic mice successfully suppressed neuroinflammation and delayed the progression.

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