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  • The EMBO Journal (2007) 26, 4149 - 4159
  • doi:10.1038/sj.emboj.7601840

Published online: 30 August 2007

D-Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis

Jumpei Sasabe1,2, Tomohiro Chiba1,2, Marina Yamada1,2, Koichi Okamoto3, Ikuo Nishimotoa, Masaaki Matsuoka1,2 and Sadakazu Aiso1,2

  1. Department of Anatomy, KEIO University School of Medicine, Shinjuku-ku, Tokyo, Japan
  2. Department of Cell Biology and Neuroscience, KEIO University School of Medicine, Shinjuku-ku, Tokyo, Japan
  3. Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

Correspondence to:

Masaaki Matsuoka, Department of Cell Biology and Neuroscience/Anatomy, KEIO University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: +81 3 5363 8427; Fax: +81 3 5363 8428; E-mail: sakimatu@sc.itc.keio.ac.jp

aTo our regret, he passed away on 17 October 2003.

Received 8 March 2007; Accepted 30 July 2007

Excitotoxicity has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). More recently, glial involvement has been shown to be essential for ALS-related motoneuronal death. Here, we identified an N-methyl-D-aspartate (NMDA) receptor co-agonist, D-serine (D-Ser), as a glia-derived enhancer of glutamate (Glu) toxicity to ALS motoneurons. Cell death assay indicated that primary spinal cord neurons from ALS mice were more vulnerable to NMDA toxicity than those from control mice, in a D-Ser-dependent manner. Levels of D-Ser and its producing enzyme, serine racemase, in spinal cords of ALS mice were progressively elevated, dominantly in glia, with disease progression. In vitro, expression of serine racemase was induced not only by an extracellular pro-inflammatory factor, but also by transiently expressed G93A-superoxide dismutase1 in microglial cells. Furthermore, increases of D-Ser levels were also observed in spinal cords of both familial and sporadic ALS patients. Collectively, Glu toxicity enhanced by D-Ser overproduced in glia is proposed as a novel mechanism underlying ALS motoneuronal death, and this mechanism may be regarded as a potential therapeutic target for ALS.

  • Keywords:

    • ALS,
    • D-serine,
    • excitotoxicity,
    • glia,
    • NMDA