Possible relationship between S-nitrosylated proteins and neurodegenerative disorders

S-亚硝基化蛋白与神经退行性疾病之间的可能关系

• 批准号: 17590050
• 负责人: UEHARA Takashi
• 金额: $ 2.24万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590050/
• 关键词: nitric oxide; ER stress; S-nitrosylation; protein-disulfide isomerase; apoptosis; neurodegeneration; Parkinson's disease; brain ischemia; PDI

Stress proteins located in the cytosol or endoplasmic reticulum (ER) participate in maintenance of cell homeostasis and development of tolerance against severe insults. In neurodegenerative diseases, a number of chaperones can ameliorate accumulation of misfolded proteins triggered by oxidative/nitrosative stress or mutated gene products. Here we show that one such ER chaperone, protein-disulfide isomerase (PDI), is S-nitrosylated in brains manifesting sporadic Parkinson's or Alzheimer's disease. Nitric oxide-induced S-nitrosylation of PDI inhibits its enzymatic activity, leads to accumulation of polyubiquitinated proteins, and activates the unfolded protein response (UPR). S-Nitrosylation also abrogates PDI-mediated attenuation of neuronal cell death triggered by ER stress or proteasome inhibition. Thus, PDI prevents neurotoxicity associated with ER stress and protein misfolding, but nitric oxide blocks this protective effect in neurodegenerative disorders via PDI S-nitrosylation.

位于细胞质或内质网（ER）中的应激蛋白参与维持细胞内稳态和对严重损伤的耐受性的发展。在神经退行性疾病中，许多分子伴侣可以改善由氧化/亚硝化应激或突变基因产物引发的错误折叠蛋白质的积累。在这里，我们表明，这样一个ER分子伴侣，蛋白质二硫键异构酶（PDI），是S-亚硝基化的大脑表现为散发性帕金森氏症或阿尔茨海默氏症。一氧化氮诱导的PDI的S-亚硝基化抑制其酶活性，导致聚泛素化蛋白的积累，并激活未折叠蛋白反应（UPR）。S-亚硝基化还消除了由ER应激或蛋白酶体抑制引发的PDI介导的神经元细胞死亡的衰减。因此，PDI防止与ER应激和蛋白质错误折叠相关的神经毒性，但一氧化氮通过PDI S-亚硝基化阻断神经退行性疾病中的这种保护作用。

项目成果

Accumulation of misfolded protein through nitrosative stress linked to neurodegenerative disorders.

• DOI: 10.1089/ars.2006.1517
• 发表时间: 2007-04
• 期刊: Antioxidants & redox signaling
• 影响因子: 6.6
• 作者: T. Uehara