Department of Pharmacology, Case Western Reserve University, 2109 Adelbert Rd, Cleveland, OH 44106, USA.
Nutrients. 2012 Oct 9;4(10):1399-440. doi: 10.3390/nu4101399.
Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, and Friedreich's ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated.
谷胱甘肽稳态的失调和谷胱甘肽依赖酶活性的改变，越来越多地与神经退行性疾病（包括阿尔茨海默病、帕金森病和亨廷顿病、肌萎缩性侧索硬化症和弗里德里希共济失调）的诱导和进展有关。在这篇综述中，提供了谷胱甘肽的稳态合成、调节和转运的背景信息，主要关注大脑。简要概述了谷胱甘肽在细胞维持和存活中的独特但至关重要的作用，以及关键谷胱甘肽依赖酶的功能。考虑了引发和促进神经退行性疾病的主要因素，包括氧化应激、蛋白质错误折叠和蛋白质聚集。在每种情况下，都确定了对谷胱甘肽氧化还原状态和/或谷胱甘肽依赖酶活性变化敏感的关键调节机制的例子。讨论了与每种神经退行性疾病发病机制相关的谷胱甘肽和/或谷胱甘肽依赖酶失调的机制。确定了信息或解释方面的局限性，并描述了进一步研究的可能途径，旨在阐明治疗干预的新靶点。批判性地评估了 N-乙酰半胱氨酸或谷胱甘肽作为神经退行性疾病治疗剂的优缺点，以及血清谷胱甘肽作为生物标志物的潜在效用。
