Nakamura Tomohiro, Prikhodko Olga A, Pirie Elaine, Nagar Saumya, Akhtar Mohd Waseem, Oh Chang-Ki, McKercher Scott R, Ambasudhan Rajesh, Okamoto Shu-ichi, Lipton Stuart A
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Biomedical Sciences Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Neurobiol Dis. 2015 Dec;84:99-108. doi: 10.1016/j.nbd.2015.03.017. Epub 2015 Mar 18.
Nitric oxide (NO) is a gasotransmitter that impacts fundamental aspects of neuronal function in large measure through S-nitrosylation, a redox reaction that occurs on regulatory cysteine thiol groups. For instance, S-nitrosylation regulates enzymatic activity of target proteins via inhibition of active site cysteine residues or via allosteric regulation of protein structure. During normal brain function, protein S-nitrosylation serves as an important cellular mechanism that modulates a diverse array of physiological processes, including transcriptional activity, synaptic plasticity, and neuronal survival. In contrast, emerging evidence suggests that aging and disease-linked environmental risk factors exacerbate nitrosative stress via excessive production of NO. Consequently, aberrant S-nitrosylation occurs and represents a common pathological feature that contributes to the onset and progression of multiple neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases. In the current review, we highlight recent key findings on aberrant protein S-nitrosylation showing that this reaction triggers protein misfolding, mitochondrial dysfunction, transcriptional dysregulation, synaptic damage, and neuronal injury. Specifically, we discuss the pathological consequences of S-nitrosylated parkin, myocyte enhancer factor 2 (MEF2), dynamin-related protein 1 (Drp1), protein disulfide isomerase (PDI), X-linked inhibitor of apoptosis protein (XIAP), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) under neurodegenerative conditions. We also speculate that intervention to prevent these aberrant S-nitrosylation events may produce novel therapeutic agents to combat neurodegenerative diseases.
一氧化氮（NO）是一种气体递质，在很大程度上通过S-亚硝基化影响神经元功能的基本方面，S-亚硝基化是一种发生在调节性半胱氨酸硫醇基团上的氧化还原反应。例如，S-亚硝基化通过抑制活性位点半胱氨酸残基或通过蛋白质结构的变构调节来调节靶蛋白的酶活性。在正常脑功能期间，蛋白质S-亚硝基化作为一种重要的细胞机制，调节多种生理过程，包括转录活性、突触可塑性和神经元存活。相比之下，新出现的证据表明，衰老和与疾病相关的环境风险因素通过过量产生NO加剧亚硝化应激。因此，异常的S-亚硝基化发生，并代表一种常见的病理特征，促成包括阿尔茨海默病、帕金森病和亨廷顿病在内的多种神经退行性疾病的发生和发展。在本综述中，我们重点介绍了关于异常蛋白质S-亚硝基化的最新关键发现，表明该反应会引发蛋白质错误折叠、线粒体功能障碍、转录失调、突触损伤和神经元损伤。具体而言，我们讨论了在神经退行性疾病条件下，S-亚硝基化的帕金、肌细胞增强因子2（MEF2）、发动蛋白相关蛋白1（Drp1）、蛋白质二硫键异构酶（PDI）、X连锁凋亡抑制蛋白（XIAP）和甘油醛-3-磷酸脱氢酶（GAPDH）的病理后果。我们还推测，预防这些异常S-亚硝基化事件的干预措施可能会产生对抗神经退行性疾病的新型治疗药物。
