Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke

作者：Qing‐zhang Tuo, Zhen‐Yu Liuyang, Peng Lei, Xiong Yan, Yangping Shentu, Jiawei Liang, Huan Zhou, Lei Pei, Yan Xiong, Tongyao Hou, Xinwen Zhou, Qun Wang, Jian‐Zhi Wang, Xiaochuan Wang, Rong Liu · 发表于：Cell Death and Disease · 年份：2018 · DOI：10.1038/s41419-018-0929-7 · 被引用次数：43 · 研究领域：Trace Elements in Health、Neuroscience and Neuropharmacology Research、Alzheimer's disease research and treatments

CDK5 activation promotes ischemic neuronal death in stroke, with the recognized activation mechanism being calpain-dependent p35 cleavage to p25. Here we reported that CDK5-Tyr15 phosphorylation by zinc induced CDK5 activation in brain ischemic injury. CDK5 activation and CDK5-Tyr15 phosphorylation were observed in the hippocampus of the rats that had been subjected to middle cerebral artery occlusion, both of which were reversed by pretreatment with zinc chelator; while p35 cleavage and calpain activation in ischemia were not reversed. Zinc incubation resulted in CDK5-Tyr15 phosphorylation and CDK5 activation, without increasing p35 cleavage in cultured cells. Site mutation experiment confirmed that zinc-induced CDK5 activation was dependent on Tyr15 phosphorylation. Further exploration showed that Src kinase contributed to zinc-induced Tyr15 phosphorylation and CDK5 activation. Src kinase inhibition or expression of an unphosphorylable mutant Y15F-CDK5 abolished Tyr15 phosphorylation, prevented CDK5 activation and protected hippocampal neurons from ischemic insult in rats. We conclude that zinc-induced CDK5-Tyr15 phosphorylation underlies CDK5 activation and promotes ischemic neuronal death in stroke.