Redox reactions induced by nitrosative stress mediate protein misfolding and mitochondrial dysfunction in neurodegenerative diseases.
Redox reactions induced by nitrosative stress mediate protein misfolding and mitochondrial dysfunction in neurodegenerative diseases.
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DOI：
10.1007/s12035-010-8113-9
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发表时间：
2010-06
影响因子：
5.1
通讯作者：
Lipton SA
中科院分区：
文献类型：
--
作者：
Gu Z;Nakamura T;Lipton SA
N-甲基-D-天冬氨酸(NMDA型)型谷氨酸受体的过度刺激至少在一定程度上是兴奋性毒性神经元损伤的原因，可能导致广泛的急慢性神经系统疾病。神经退行性疾病包括阿尔茨海默病(AD)和帕金森病(PD)，表现为错误折叠或聚集的蛋白质沉积，由突触损伤和神经元死亡引起。最近的研究表明，由于产生过量的一氧化氮(NO)而导致的亚硝化性应激，在没有遗传易感性的情况下，部分地通过触发蛋白质的错误折叠和聚集以及线粒体的碎裂来介导兴奋性毒性。S-亚硝化，即NO与特定蛋白质硫醇基团的共价反应，是一条汇聚的信号通路，导致NO诱导的蛋白质错误折叠和聚集，破坏线粒体分裂-融合过程的动力学，从而导致神经毒性。在此，我们综述了S亚硝化对兴奋性毒性条件下蛋白质功能的影响，并提出证据表明，NO通过S亚硝化蛋白二硫键异构酶或E3泛素连接酶PARKIN参与蛋白质的错误折叠和聚集，以及通过β淀粉样蛋白相关的S亚硝化动力蛋白相关蛋白1而导致线粒体断裂。此外，我们还讨论了非竞争性/快失速(UFO)药物美金刚抑制过度的NMDA受体活性可以改善NO的过度产生、蛋白质的错误折叠和聚集、线粒体的碎裂和神经变性。
Overstimulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors accounts, at least in part, for excitotoxic neuronal damage, potentially contributing to a wide range of acute and chronic neurologic diseases. Neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD), manifest deposits of misfolded or aggregated proteins, and result from synaptic injury and neuronal death. Recent studies have suggested that nitrosative stress due to generation of excessive nitric oxide (NO) can mediate excitotoxicity in part by triggering protein misfolding and aggregation, and mitochondrial fragmentation in the absence of genetic predisposition. S-Nitrosylation, or covalent reaction of NO with specific protein thiol groups, represents a convergent signal pathway contributing to NO-induced protein misfolding and aggregation, compromised dynamics of mitochondrial fission-fusion process, thus leading to neurotoxicity. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence suggesting that NO contributes to protein misfolding and aggregation via S-nitrosylating protein-disulfide isomerase or the E3 ubiquitin ligase parkin, and mitochondrial fragmentation through β-amyloid-related S-nitrosylation of dynamin-related protein-1. Moreover, we also discuss that inhibition of excessive NMDA receptor activity by memantine, an uncompetitive/fast off-rate (UFO) drug can ameliorate excessive production of NO, protein misfolding and aggregation, mitochondrial fragmentation, and neurodegeneration.