D-Amino acid oxidase controls motoneuron degeneration through D-serine
D-Amino acid oxidase controls motoneuron degeneration through D-serine
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DOI：
10.1073/pnas.1114639109
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发表时间：
2012-01-10
影响因子：
11.1
通讯作者：
Aiso, Sadakazu
中科院分区：
文献类型：
--
作者：
Sasabe, Jumpei;Miyoshi, Yurika;Aiso, Sadakazu
肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种以运动神经元广泛缺失为特征的神经退行性疾病。运动神经元的异常兴奋性与ALS中选择性运动神经元死亡的发病机制有关。D-丝氨酸是N-甲基-D-天冬氨酸受体的内源性促凝剂，可加剧运动神经元死亡，并且在散发性/家族性ALS患者和ALS的G93 A-SOD 1小鼠模型（mSOD 1小鼠）中均增加。最近，在D-氨基酸氧化酶（DAO）基因，编码D-丝氨酸降解酶的一个独特的突变，据报道与经典的家族性ALS。然而，DAO是否影响ALS的运动神经元表型和D-丝氨酸增加仍不确定。在这里，我们表明，在小鼠中的DAO基因失活减少了轴突变性的较低运动神经元的数量和大小，并抑制DAO活性的反应性星形胶质细胞在网状脊髓束，一个主要的输入到较低的运动神经元，主要是有助于D-丝氨酸增加mSOD 1小鼠。DAO的不活动导致表达下调，这是由谷氨酸受体和MEK的抑制剂逆转，但不是由那些炎症刺激。我们的研究结果提供的证据表明，DAO通过D-丝氨酸调节在运动神经元变性中具有关键作用，并且DAO的不活动是mSOD 1 ALS小鼠模型和突变DAO相关家族性ALS之间的共同特征。在ALS中减少D-丝氨酸或控制DAO活性的治疗益处应在未来的研究中进行测试。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving an extensive loss of motoneurons. Aberrant excitability of motoneurons has been implicated in the pathogenesis of selective motoneuronal death in ALS. D-Serine, an endogenous coagonist of N-methyl-D-aspartate receptors, exacerbates motoneuronal death and is increased both in patients with sporadic/familial ALS and in a G93A-SOD1 mouse model of ALS (mSOD1 mouse). More recently, a unique mutation in the D-amino acid oxidase (DAO) gene, encoding a D-serine degrading enzyme, was reported to be associated with classical familial ALS. However, whether DAO affects the motoneuronal phenotype and D-serine increase in ALS remains uncertain. Here, we show that genetic inactivation of DAO in mice reduces the number and size of lower motoneurons with axonal degeneration, and that suppressed DAO activity in reactive astrocytes in the reticulospinal tract, one of the major inputs to the lower motoneurons, predominantly contributes to the D-serine increase in the mSOD1 mouse. The DAO inactivity resulted from expressional down-regulation, which was reversed by inhibitors of a glutamate receptor and MEK, but not by those of inflammatory stimuli. Our findings provide evidence that DAO has a pivotal role in motoneuron degeneration through D-serine regulation and that inactivity of DAO is a common feature between the mSOD1 ALS mouse model and the mutant DAO-associated familial ALS. The therapeutic benefit of reducing D-serine or controlling DAO activity in ALS should be tested in future studies.