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

Miki Oono, Ayako Okado-Matsumoto, Akemi Shodai, Akemi Ido, Yasuyuki Ohta, Koji Abe, Takashi Ayaki, Hidefumi Ito, Ryosuke Takahashi, Naoyuki Taniguchi, Makoto Urushitani

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)403-418
Number of pages16
JournalJournal of Neurochemistry
Volume128
Issue number3
DOIs
Publication statusPublished - Feb 1 2014

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Keywords

  • amyotrophic lateral sclerosis
  • microglia
  • non-cell-autonomous
  • oligomer
  • superoxide dismutase 1
  • transglutaminase 2

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Oono, M., Okado-Matsumoto, A., Shodai, A., Ido, A., Ohta, Y., Abe, K., Ayaki, T., Ito, H., Takahashi, R., Taniguchi, N., & Urushitani, M. (2014). Transglutaminase 2 accelerates neuroinflammation in amyotrophic lateral sclerosis through interaction with misfolded superoxide dismutase 1. Journal of Neurochemistry, 128(3), 403-418. https://doi.org/10.1111/jnc.12441