抄録
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
Abnormal D-serine metabolism in amyotrophic lateral sclerosis. / Sasabe, Jumpei; Aiso, Sadakazu.
D-Amino Acids: Physiology, Metabolism, and Application. Springer Japan, 2016. p. 137-149.研究成果: Chapter
}
TY - CHAP
T1 - Abnormal D-serine metabolism in amyotrophic lateral sclerosis
AU - Sasabe, Jumpei
AU - Aiso, Sadakazu
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
KW - Amyotrophic lateral sclerosis
KW - D-amino acid oxidase
KW - D-Serine
KW - Motoneuron
KW - Serine racemase
UR - http://www.scopus.com/inward/record.url?scp=85017089968&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85017089968&partnerID=8YFLogxK
U2 - 10.1007/978-4-431-56077-7_9
DO - 10.1007/978-4-431-56077-7_9
M3 - Chapter
AN - SCOPUS:85017089968
SN - 9784431560753
SP - 137
EP - 149
BT - D-Amino Acids
PB - Springer Japan
ER -