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 journalArticlepeer-review

202 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

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Fingerprint Dive into the research topics of 'D-Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis'. Together they form a unique fingerprint.

Cite this