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

Jumpei Sasabe, Tomohiro Chiba, Marina Yamada, Koichi Okamoto, Ikuo Nishimoto, Masaaki Matsuoka, Sadakazu Aiso

Research output: Contribution to journalArticle

184 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4149-4159
Number of pages11
JournalEMBO Journal
Volume26
Issue number18
DOIs
Publication statusPublished - 2007 Sep 19
Externally publishedYes

Fingerprint

Serine
Toxicity
Glutamic Acid
Cell death
N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Superoxides
Neurons
Assays
Neuroglia
Enzymes
serine racemase

Keywords

  • ALS
  • D-serine
  • Excitotoxicity
  • Glia
  • NMDA

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Sasabe, J., Chiba, T., Yamada, M., Okamoto, K., Nishimoto, I., Matsuoka, M., & Aiso, S. (2007). D-Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis. EMBO Journal, 26(18), 4149-4159. https://doi.org/10.1038/sj.emboj.7601840

D-Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis. / Sasabe, Jumpei; Chiba, Tomohiro; Yamada, Marina; Okamoto, Koichi; Nishimoto, Ikuo; Matsuoka, Masaaki; Aiso, Sadakazu.

In: EMBO Journal, Vol. 26, No. 18, 19.09.2007, p. 4149-4159.

Research output: Contribution to journalArticle

Sasabe, J, Chiba, T, Yamada, M, Okamoto, K, Nishimoto, I, Matsuoka, M & Aiso, S 2007, 'D-Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis', EMBO Journal, vol. 26, no. 18, pp. 4149-4159. https://doi.org/10.1038/sj.emboj.7601840
Sasabe J, Chiba T, Yamada M, Okamoto K, Nishimoto I, Matsuoka M et al. D-Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis. EMBO Journal. 2007 Sep 19;26(18):4149-4159. https://doi.org/10.1038/sj.emboj.7601840
Sasabe, Jumpei ; Chiba, Tomohiro ; Yamada, Marina ; Okamoto, Koichi ; Nishimoto, Ikuo ; Matsuoka, Masaaki ; Aiso, Sadakazu. / D-Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis. In: EMBO Journal. 2007 ; Vol. 26, No. 18. pp. 4149-4159.
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