Accumulation of misfolded protein through nitrosative stress linked to neurodegenerative disorders.
Accumulation of misfolded protein through nitrosative stress linked to neurodegenerative disorders.
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DOI：
10.1089/ars.2006.1517
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发表时间：
2007-04
影响因子：
6.6
通讯作者：
T. Uehara
中科院分区：
文献类型：
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作者：
T. Uehara
蛋白质质量控制是细胞内稳态的一个关键特征。特别是，由环境压力或自由基导致的未折叠或错误折叠的蛋白质会通过泛素 - 蛋白酶体途径迅速降解。一氧化氮（NO），一种自由基气体，据报道参与诸如血管舒张和神经传递等过程。相反，NO也与神经元细胞死亡或神经退行性变有关。近期的报道表明，蛋白质的S - 亚硝基化是导致神经功能障碍进而引发神经退行性疾病的一个重要原因。具体而言，帕金蛋白的S - 亚硝基化最终导致未折叠蛋白质的积累以及随后的神经元死亡。本综述的重点是NO作用靶点的确定。亚硝基化应激通过位于内质网腔的蛋白质二硫键异构酶（PDI）的S - 亚硝基化阻止内质网（ER）的正常功能。这可能导致错误折叠蛋白质的积累以及未折叠蛋白质反应（UPR）途径的持续激活。这些现象可能与散发性神经退行性疾病的发展有关。
Protein quality control is a critical feature of intracellular homeostasis. In particular, unfolded or misfolded proteins resulting from environmental stresses or free radicals are rapidly degraded via the ubiquitin-proteasome pathway. Nitric oxide (NO), a free radical gas, has been reported to be involved in such processes as vasorelaxation and neurotransmission. Conversely, NO also is implicated in neuronal cell death or neurodegeneration. Recent reports suggest that S-nitrosylation of proteins is a significant cause of neural dysfunction leading to neurodegenerative disorders. Specifically, S-nitrosylation of parkin eventually leads to the accumulation of unfolded proteins and subsequent neuronal death. The focus of this review is the identity of the target of NO. Nitrosative stress prevents normal functioning of the endoplasmic reticulum (ER) via S-nitrosylation of protein-disulfide isomerase (PDI), which is located in the ER lumen. This may contribute to the accumulation of misfolded proteins, as well as sustained activation of the unfolded protein response (UPR) pathway. These phenomena may be linked to the development of sporadic neurodegenerative diseases.