Department of Anesthesiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Commun Biol. 2024 Sep 10;7(1):1113. doi: 10.1038/s42003-024-06832-z.
Alzheimer's disease (AD), characterized by cognitive decline, is increasingly recognized as a disorder marked by synaptic loss and dysfunction. Despite this understanding, the underlying pathophysiological mechanisms contributing to synaptic impairment remain largely unknown. In this study, we elucidate a previously undiscovered signaling pathway wherein the S-nitrosylation of the Cdk5 activator p39, a post-translational modification involving the addition of nitric oxide to protein cysteine residues, plays a crucial role in synaptic dysfunction associated with AD. Our investigation reveals heightened p39 S-nitrosylation in the brain of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD. Additionally, soluble amyloid-β oligomers (Aβ), implicated in synaptic loss in AD, induce p39 S-nitrosylation in cultured neurons. Notably, we uncover that p39 protein level is regulated by S-nitrosylation, with nitric oxide S-nitrosylating p39 at Cys265 and subsequently promoting its degradation. Furthermore, our study demonstrates that S-nitrosylation of p39 at Cys265 significantly contributes to amyloid-β (Aβ) peptide-induced dendrite retraction and spine loss. Collectively, our findings highlight S-nitrosylation of p39 as a novel aberrant redox protein modification involved in the pathogenesis of AD, suggesting its potential as a therapeutic target for the disease.
阿尔茨海默病（AD）以认知能力下降为特征，越来越被认为是一种以突触丧失和功能障碍为特征的疾病。尽管有了这种认识，但导致突触损伤的潜在病理生理机制在很大程度上仍不清楚。在这项研究中，我们阐明了一个以前未被发现的信号通路，其中 Cdk5 激活剂 p39 的 S-亚硝基化，即涉及将一氧化氮添加到蛋白质半胱氨酸残基的翻译后修饰，在与 AD 相关的突触功能障碍中发挥关键作用。我们的研究表明，在 AD 的淀粉样前体蛋白（APP）/早老素 1（PS1）转基因小鼠模型的大脑中，p39 的 S-亚硝基化水平升高。此外，可溶性淀粉样β寡聚物（Aβ），与 AD 中的突触丧失有关，可诱导培养神经元中的 p39 S-亚硝基化。值得注意的是，我们发现 p39 蛋白水平受 S-亚硝基化调节，一氧化氮将 p39 的 Cys265 亚硝基化，随后促进其降解。此外，我们的研究表明，p39 的 Cys265 上的 S-亚硝基化显著导致 Aβ 肽诱导的树突回缩和棘突丢失。总之，我们的研究结果强调了 p39 的 S-亚硝基化作为 AD 发病机制中涉及的新型异常氧化还原蛋白修饰，表明其作为该疾病治疗靶点的潜力。
