Glutathione and Related Molecules in Parkinsonism.
Glutathione and Related Molecules in Parkinsonism.
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DOI：
10.3390/ijms22168689
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发表时间：
2021-08-13
影响因子：
5.6
通讯作者：
Miyazaki I
中科院分区：
文献类型：
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作者：
Asanuma M;Miyazaki I
谷胱甘肽(GSH)是中枢神经系统中含量最丰富的内源性抗氧化剂，其底物半胱氨酸很容易成为氧化的二聚半胱氨酸。由于神经元缺乏半胱氨酸转运系统，神经元GSH的合成依赖于半胱氨酸/谷氨酸交换转运体(XCT)对半胱氨酸的摄取、GSH的合成和周围星形胶质细胞的释放。转录因子核因子红系2相关因子(Nrf2)是一种主要在星形胶质细胞中表达的解毒转录因子，通过与抗氧化剂反应元件(ARE)结合，激活多种药物代谢酶或抗氧化剂的基因表达，包括GSH相关分子和金属硫蛋白。越来越多的证据表明，包括GSH及其相关分子在内的抗氧化分子功能障碍参与了帕金森病(PD)或帕金森病模型的发病过程。此外，我们发现了几种针对星形胶质细胞中GSH合成的药物，它们可以保护帕金森病模型中黑质纹状体多巴胺能神经元的丢失。本文综述了补充和增强GSH及其相关分子在PD病理中的神经保护作用，并介绍了新的实验结果，特别是针对星形胶质细胞中XCT-GSH合成系统和Nrf2-ARE途径的研究。
Glutathione (GSH) is the most abundant intrinsic antioxidant in the central nervous system, and its substrate cysteine readily becomes the oxidized dimeric cystine. Since neurons lack a cystine transport system, neuronal GSH synthesis depends on cystine uptake via the cystine/glutamate exchange transporter (xCT), GSH synthesis, and release in/from surrounding astrocytes. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a detoxifying master transcription factor, is expressed mainly in astrocytes and activates the gene expression of various phase II drug-metabolizing enzymes or antioxidants including GSH-related molecules and metallothionein by binding to the antioxidant response element (ARE) of these genes. Accumulating evidence has shown the involvement of dysfunction of antioxidative molecules including GSH and its related molecules in the pathogenesis of Parkinson’s disease (PD) or parkinsonian models. Furthermore, we found several agents targeting GSH synthesis in the astrocytes that protect nigrostriatal dopaminergic neuronal loss in PD models. In this article, the neuroprotective effects of supplementation and enhancement of GSH and its related molecules in PD pathology are reviewed, along with introducing new experimental findings, especially targeting of the xCT-GSH synthetic system and Nrf2–ARE pathway in astrocytes.