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D ‐Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis
Author(s) -
Sasabe Jumpei,
Chiba Tomohiro,
Yamada Marina,
Okamoto Koichi,
Nishimoto Ikuo,
Matsuoka Masaaki,
Aiso Sadakazu
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601840
Subject(s) - amyotrophic lateral sclerosis , excitotoxicity , biology , glutamate receptor , nmda receptor , sod1 , toxicity , programmed cell death , microbiology and biotechnology , receptor , biochemistry , superoxide dismutase , apoptosis , pathology , medicine , enzyme , disease
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.