Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases.
Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases.
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DOI：
10.1016/j.nbd.2015.03.017
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发表时间：
2015-12
影响因子：
6.1
通讯作者：
Lipton SA
中科院分区：
文献类型：
--
作者：
Nakamura T;Prikhodko OA;Pirie E;Nagar S;Akhtar MW;Oh CK;McKercher SR;Ambasudhan R;Okamoto S;Lipton SA
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（一种发生在调节性半胱氨酸硫醇基上的氧化还原反应）影响神经元功能的基本方面。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。在正常的大脑功能中，蛋白质 S-亚硝基化是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会通过过量产生一氧化氮而加剧亚硝化应激。因此，异常的 S-亚硝基化发生并代表了一种常见的病理特征，导致多种神经退行性疾病的发生和进展，包括阿尔茨海默病、帕金森病和亨廷顿病。在当前的综述中，我们重点介绍了异常蛋白质 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。具体来说，我们讨论了 S-亚硝基化 Parkin、肌细胞增强因子 2 (MEF2)、动力相关蛋白 1 (Drp1)、蛋白二硫键异构酶 (PDI)、X 连锁凋亡抑制蛋白 (XIAP) 和 3-磷酸甘油醛脱氢酶 (GAPDH) 的病理后果。 神经退行性疾病。我们还推测，预防这些异常 S-亚硝基化事件的干预可能会产生新的治疗药物来对抗神经退行性疾病。
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 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.