Possible relationship between S-nitrosylated proteins and neurodegenerative disorders

位于细胞质或内质网（ER）的应激蛋白参与细胞稳态的维持和对严重损伤的耐受性的发展。在神经退行性疾病中，一些伴侣蛋白可以改善氧化/亚硝化应激或突变基因产物引发的错误折叠蛋白的积累。在这里，我们发现一种这样的内质网伴侣蛋白二硫异构酶（PDI）在散发性帕金森病或阿尔茨海默病的大脑中被s -亚硝基化。一氧化氮诱导的PDI s -亚硝基化抑制其酶活性，导致多泛素化蛋白的积累，并激活未折叠蛋白反应（UPR）。s -亚硝基化也消除了pdi介导的内质网应激或蛋白酶体抑制引发的神经元细胞死亡的衰减。因此，PDI可以预防内质网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 -亚硝基化阻断了神经退行性疾病的这种保护作用。

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.