Abnormal D-serine metabolism in amyotrophic lateral sclerosis

Jumpei Sasabe, Sadakazu Aiso

研究成果: Chapter

2 引用 (Scopus)

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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.

元の言語English
ホスト出版物のタイトルD-Amino Acids
ホスト出版物のサブタイトルPhysiology, Metabolism, and Application
出版者Springer Japan
ページ137-149
ページ数13
ISBN(電子版)9784431560777
ISBN(印刷物)9784431560753
DOI
出版物ステータスPublished - 2016 1 1
外部発表Yes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

これを引用

Sasabe, J., & Aiso, S. (2016). Abnormal D-serine metabolism in amyotrophic lateral sclerosis. : D-Amino Acids: Physiology, Metabolism, and Application (pp. 137-149). Springer Japan. https://doi.org/10.1007/978-4-431-56077-7_9