Abnormal D-serine metabolism in amyotrophic lateral sclerosis

Jumpei Sasabe, Sadakazu Aiso

Research output: Chapter in Book/Report/Conference proceedingChapter

3 Citations (Scopus)


Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, whose pathology is characterized by death of upper and lower motor neurons, inclusion bodies in remaining neurons and glia, and glial activation around the neurons. The pathophysiological mechanisms underlying ALS are multifactorial and remain to be fully elucidated. Here, we review D-serine-related findings in ALS and delineate how D-serine metabolism is disturbed and why such D-serine derangement could potentially be toxic to motoneurons. Motoneurons are vulnerable to glutamate excitotoxicity. D-Serine is an endogenous coagonist with glutamate for stimulation of N-methyl-D-aspartate (NMDA) subtype glutamate receptors. D-Serine accumulates progressively in the spinal cord of a mouse model of familial ALS, in which human superoxide dismutase 1 (SOD1) with a mutation G93A is overexpressed. Such accumulation was also reported in a few patients with sporadic ALS or familial ALS with A4T-SOD1. The D-serine accumulation in the mouse model is explained by a combination of increased D-serine-producing enzyme and decreased D-serine-degrading enzyme, D-amino acid oxidase (DAO), which are both found in activated glial cells. Importantly, a dominant negative mutation D199W in DAO has been reported in patients with familial ALS that exhibits classical motor symptoms of ALS. The mutant D199W-DAO increases autophagy in motor neurons through activation of NMDA receptors by D-serine, which results in motoneuronal apoptosis. Furthermore, a null mutation G181R in DAO significantly increases D-serine level in the spinal cord with mild motoneuronal degeneration in mice. Collectively, aberrant metabolism of D-serine in glial cells may trigger motoneuronal degeneration, which sheds light on a unique aspect of ALS pathophysiology.

Original languageEnglish
Title of host publicationD-Amino Acids: Physiology, Metabolism, and Application
PublisherSpringer Japan
Number of pages13
ISBN (Electronic)9784431560777
ISBN (Print)9784431560753
Publication statusPublished - 2016 Jan 1


  • Amyotrophic lateral sclerosis
  • D-amino acid oxidase
  • D-Serine
  • Motoneuron
  • Serine racemase

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology


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