Molecular Mechanisms of Glutamate Toxicity in Parkinson's Disease.
Molecular Mechanisms of Glutamate Toxicity in Parkinson's Disease.
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帕金森病谷氨酸毒性的分子机制
DOI：
10.3389/fnins.2020.585584
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发表时间：
2020
影响因子：
4.3
通讯作者：
Qu S
中科院分区：
文献类型：
--
作者：
Wang J;Wang F;Mai D;Qu S
帕金森病（Parkinson's disease，PD）是一种常见的神经退行性疾病，其病理特征包括黑质白质内存在Lewy小体和多巴胺能神经元变性。然而，直到最近，PD的发病机制和治疗的研究进展缓慢。谷氨酸和多巴胺都是哺乳动物重要的中枢神经递质。缺乏胞外谷氨酸的酶促分解导致谷氨酸在突触处积聚，其主要被兴奋性氨基酸转运体（EAAT）吸收。谷氨酸通过结合并激活配体门控离子通道[离子型谷氨酸受体（iGluRs）]和一类G蛋白偶联受体[代谢型谷氨酸受体（mGluRs）]发挥其生理作用。及时清除突触间隙中的谷氨酸是必要的，因为高水平的细胞外谷氨酸过度激活谷氨酸受体，导致中枢神经系统中的兴奋性毒性作用。此外，细胞外谷氨酸浓度增加抑制胱氨酸摄取，导致谷胱甘肽耗竭和氧化谷氨酸毒性。研究表明，缺乏功能性N-甲基-D-天冬氨酸（NMDA）受体的神经元中的氧化谷氨酸毒性可能是兴奋性毒性诱导的细胞死亡途径的一个组成部分。炎症和兴奋性毒性之间的关联（即，免疫兴奋毒性）近年来受到越来越多的关注。神经胶质活化诱导神经炎症，并可刺激谷氨酸的过度释放，这可诱导兴奋性毒性，此外，进一步加剧神经炎症。谷氨酸作为一种重要的中枢神经递质，与PD的发生、发展密切相关。本文就谷氨酸作为PD相关神经递质的研究进展作一综述。此外，本文还综述了谷氨酸兴奋毒性、氧化毒性和免疫兴奋毒性之间的关系和共性，以期从整体上了解谷氨酸毒性在PD中的作用及其分子机制。
Parkinson’s disease (PD) is a common neurodegenerative disease, the pathological features of which include the presence of Lewy bodies and the neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta. However, until recently, research on the pathogenesis and treatment of PD have progressed slowly. Glutamate and dopamine are both important central neurotransmitters in mammals. A lack of enzymatic decomposition of extracellular glutamate results in glutamate accumulating at synapses, which is mainly absorbed by excitatory amino acid transporters (EAATs). Glutamate exerts its physiological effects by binding to and activating ligand-gated ion channels [ionotropic glutamate receptors (iGluRs)] and a class of G-protein-coupled receptors [metabotropic glutamate receptors (mGluRs)]. Timely clearance of glutamate from the synaptic cleft is necessary because high levels of extracellular glutamate overactivate glutamate receptors, resulting in excitotoxic effects in the central nervous system. Additionally, increased concentrations of extracellular glutamate inhibit cystine uptake, leading to glutathione depletion and oxidative glutamate toxicity. Studies have shown that oxidative glutamate toxicity in neurons lacking functional N-methyl-D-aspartate (NMDA) receptors may represent a component of the cellular death pathway induced by excitotoxicity. The association between inflammation and excitotoxicity (i.e., immunoexcitotoxicity) has received increased attention in recent years. Glial activation induces neuroinflammation and can stimulate excessive release of glutamate, which can induce excitotoxicity and, additionally, further exacerbate neuroinflammation. Glutamate, as an important central neurotransmitter, is closely related to the occurrence and development of PD. In this review, we discuss recent progress on elucidating glutamate as a relevant neurotransmitter in PD. Additionally, we summarize the relationship and commonality among glutamate excitotoxicity, oxidative toxicity, and immunoexcitotoxicity in order to posit a holistic view and molecular mechanism of glutamate toxicity in PD.
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