Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, 226001, China.
Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, 10314, USA.
Sci Rep. 2017 Sep 6;7(1):10686. doi: 10.1038/s41598-017-10635-0.
O-GlcNAcylation is a common posttranslational modification of nucleocytoplasmic proteins with β-N-acetylglucosamine (GlcNAc) and regulates numerous biological processes. By using mouse models of cerebral ischemia induced by permanent and transient middle cerebral artery occlusion (MCAO), we observed an initial elevation (~1.7-fold, 1-4 hours after ischemia) and then decline of O-GlcNAcylation during cerebral ischemia. We found that moderate increase (<3-fold) of brain O-GlcNAcylation by pharmacological means ameliorated cerebral ischemia-reperfusion injury and the consequent motor and neurological deficits. Interference of the transient elevation of O-GlcNAcylation pharmacologically or genetically aggravates the ischemia-induced brain damage, motor deficits and mortality. The alteration of O-GlcNAcylation was also seen in the ischemic areas of postmortem human brains. This study reveals an important regulation of cerebral ischemia-reperfusion injury by O-GlcNAcylation and also provides a possible therapeutic strategy, i.e., by increasing O-GlcNAcylation, to reduce the cerebral damage and improve the clinical outcome of ischemic stroke.
O-GlcNAcylation 是一种常见的核质蛋白的翻译后修饰，其带有β-N-乙酰葡萄糖胺（GlcNAc），并调节着众多的生物进程。通过使用永久性和短暂性大脑中动脉阻塞（MCAO）诱导的脑缺血的小鼠模型，我们在脑缺血期间观察到 O-GlcNAcylation 的初始升高（~1.7 倍，缺血后 1-4 小时），随后下降。我们发现，通过药理学手段适度增加（<3 倍）脑 O-GlcNAcylation 可改善脑缺血再灌注损伤以及随后的运动和神经功能缺损。O-GlcNAcylation 的短暂升高的药理学或遗传学干扰会加重缺血引起的脑损伤、运动障碍和死亡率。O-GlcNAcylation 的改变也见于死后人脑的缺血区域。这项研究揭示了 O-GlcNAcylation 对脑缺血再灌注损伤的重要调节作用，并提供了一种可能的治疗策略，即通过增加 O-GlcNAcylation 来减轻脑损伤并改善缺血性中风的临床转归。
