D-Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis
D-Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis
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DOI：
10.1038/sj.emboj.7601840
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发表时间：
2007-09-19
期刊：
影响因子：
11.4
通讯作者：
Aiso, Sadakazu
中科院分区：
文献类型：
--
作者：
Sasabe, Jumpei;Chiba, Tomohiro;Aiso, Sadakazu
兴奋性毒性与肌萎缩侧索硬化症 (ALS) 的发病机制有关。最近，神经胶质细胞的参与已被证明对于 ALS 相关的运动神经元死亡至关重要。在这里，我们鉴定了一种 N-甲基-D-天冬氨酸 (NMDA) 受体共激动剂 D-丝氨酸 (D-Ser)，作为 ALS 运动神经元的谷氨酸 (Glu) 毒性的神经胶质细胞衍生增强剂。细胞死亡测定表明，ALS 小鼠的原代脊髓神经元比对照小鼠的原代脊髓神经元更容易受到 NMDA 毒性的影响，且呈 D-Ser 依赖性方式。随着疾病的进展，ALS 小鼠脊髓中的 D-Ser 及其产生酶丝氨酸消旋酶的水平逐渐升高，主要是在神经胶质细胞中。在体外，丝氨酸消旋酶的表达不仅受到细胞外促炎因子的诱导，而且受到小胶质细胞中瞬时表达的G93A-超氧化物歧化酶1的诱导。此外，在家族性和散发性 ALS 患者的脊髓中也观察到 D-Ser 水平增加。总的来说，神经胶质细胞中过量产生的 D-Ser 增强的 Glu 毒性被认为是 ALS 运动神经元死亡的一种新机制，并且该机制可能被视为 ALS 的潜在治疗靶点。
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.