期刊
JOURNAL OF NEUROCHEMISTRY
卷 120, 期 4, 页码 598-610出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2011.07601.x
关键词
ALS; DAO; d-serine; excitotoxicity; serine racemase; SOD1
资金
- Canadian Institutes of Health Research
- CIHR [MOP 111198]
- National Institute on Aging/NIH [P01AG012411, 5R01NS040819-08]
- Thomas May Center for ALS Research and Translational Medicine
d-Serine is an endogenous neurotransmitter that binds to the NMDA receptor, thereby increasing the affinity for glutamate, and the potential for excitotoxicity. The primary source of d-serine in vivo is enzymatic racemization by serine racemase (SR). Regulation of d-serine in vivo is poorly understood, but is thought to involve a combination of controlled production, synaptic reuptake by transporters, and intracellular degradation by d-amino acid oxidase (DAO). However, SR itself possesses a well-characterized eliminase activity, which effectively degrades d-serine as well. d-Serine is increased two-fold in spinal cords of G93A Cu,Zn-superoxide dismutase (SOD1) mice the standard model of amyotrophic lateral sclerosis (ALS). ALS mice with SR disruption show earlier symptom onset, but survive longer (progression phase is slowed), in an SR-dependent manner. Paradoxically, administration of d-serine to ALS mice dramatically lowers cord levels of d-serine, leading to changes in the onset and survival very similar to SR deletion. d-Serine treatment also increases cord levels of the alanineserinecysteine transporter 1 (Asc-1). Although the mechanism by which SOD1 mutations increases d-serine is not known, these results strongly suggest that SR and d-serine are fundamentally involved in both the pre-symptomatic and progression phases of disease, and offer a direct link between mutant SOD1 and a glial-derived toxic mediator.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据