D-serine Is a Key Determinant of Glutamate Toxicity in Amyotrophic Lateral Sclerosis

EMBO J. 2007 Sep 19;26(18):4149-59. doi: 10.1038/sj.emboj.7601840. Epub 2007 Aug 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / etiology*
  • Animals
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Enzyme Induction / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Glutamic Acid / toxicity*
  • Humans
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Motor Neurons / drug effects
  • Motor Neurons / pathology
  • Mutation / genetics
  • N-Methylaspartate / toxicity
  • Neuroglia / drug effects
  • Neuroglia / enzymology
  • Racemases and Epimerases / antagonists & inhibitors
  • Racemases and Epimerases / biosynthesis
  • Racemases and Epimerases / genetics
  • Serine / metabolism*
  • Spinal Cord / drug effects
  • Spinal Cord / pathology
  • Superoxide Dismutase / metabolism
  • Up-Regulation / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Glutamic Acid
  • Serine
  • N-Methylaspartate
  • Superoxide Dismutase
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Racemases and Epimerases
  • serine racemase