Department of Geriatric Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
Department of Neurosurgery, Comprehensive Surgical Laboratory, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, China.
Cell Mol Neurobiol. 2017 Nov;37(8):1465-1475. doi: 10.1007/s10571-017-0477-1. Epub 2017 Feb 25.
Ischemic stroke is a dominant health problem with extremely high rates of mortality and disability. The main mechanism of neuronal injury after stroke is excitotoxicity, during which the activation of neuronal nitric oxide synthase (nNOS) exerts a vital role. However, directly blocking N-methyl-D-aspartate receptors or nNOS can lead to severe undesirable effects since they have crucial physiological functions in the central nervous system. Here, we report that nNOS undergoes O-linked-β-N-acetylglucosamine (O-GlcNAc) modification via interacting with O-GlcNAc transferase, and the O-GlcNAcylation of nNOS remarkably increases during glutamate-induced excitotoxicity. In addition, eliminating the O-GlcNAcylation of nNOS protects neurons from apoptosis during glutamate stimulation by decreasing the formation of nNOS-postsynaptic density protein 95 complexes. Taken together, our data suggest a novel function of the O-GlcNAcylation of nNOS in neuronal apoptosis during glutamate excitotoxicity, suggesting a novel therapy strategy for ischemic stroke.
缺血性中风是一个主要的健康问题，具有极高的死亡率和残疾率。中风后神经元损伤的主要机制是兴奋性毒性，在此过程中神经元型一氧化氮合酶（nNOS）的激活起着至关重要的作用。然而，直接阻断 N-甲基-D-天冬氨酸受体或 nNOS 可能会导致严重的不良反应，因为它们在中枢神经系统中具有重要的生理功能。在这里，我们报告 nNOS 通过与 O-连接的β-N-乙酰葡萄糖胺（O-GlcNAc）转移酶相互作用发生 O-连接的β-N-乙酰葡萄糖胺（O-GlcNAc）修饰，并且在谷氨酸诱导的兴奋性毒性过程中 nNOS 的 O-GlcNAc 化显著增加。此外，通过减少 nNOS-突触后密度蛋白 95 复合物的形成，消除 nNOS 的 O-GlcNAc 化可在谷氨酸刺激下保护神经元免于凋亡。总之，我们的数据表明 nNOS 的 O-GlcNAc 化在谷氨酸兴奋性毒性中的神经元凋亡中具有新的功能，为缺血性中风提供了一种新的治疗策略。
