14-3-3ζ介导CDK5和GSK3β促tau蛋白过度磷酸化：糖尿病早期视网膜神经节细胞变性的新机制

Tau蛋白过度磷酸化是中枢神经退行性疾病的主要表现，但其与糖尿病视网膜病变（DR）早期视网膜神经节细胞（RGCs）变性的关系未明。CDK5和GSK3β的异常激活是tau蛋白过度磷酸化的主要诱因，14-3-3蛋白可作为“接头”蛋白募集各种激酶促进tau蛋白的磷酸化。我们前期工作发现糖尿病鼠视网膜tau蛋白磷酸化增多，伴有14-3-3ζ、CDK5和激活型GSK3β表达增多。本研究拟在db/db糖尿病小鼠及高糖高脂培养的原代RGCs模型中，明确：1）tau蛋白过度磷酸化在DR早期RGCs变性中的作用；2）14-3-3ζ、CDK5和GSK3β在DR早期RGCs内tau蛋白过度磷酸化的作用及相互关系；3）14-3-3ζ是否通过结合tau与CDK5或GSK3β，促进其对tau蛋白的磷酸化。结果有望阐明DR早期RGCs变性的潜在机制，为DR的早期预防和治疗提供全新的靶点。

Hyperphosphorylation of tau in neurons is the mainly manifestation in CNS degenerative diseases, however, whether hyperphosphorylated-tau has the effect on the degeneartion of retinal ganglion cells (RGCs) in the early stage of diabetic retinopathy (DR) remains to be elucidated. Abnormal activation of GSK3β and CDK5 is the major inducement of tau hyperphosphorylation, whereas 14-3-3 protein can promote tau phosphorylation by recruiting a variety of protein kinases and act as an "Adaptor". Our preliminary results revealed an increased tau phosphorylation in the retina of diabetic mice, accompanied with an increased expression of 14-3-3ζ, CDK5 and activated GSK3β. By using db/db mice as in vivo diabetic models and primary RGCs incubated with high levels of glucose and fatty acid as in vitro glucolipotoxicity models, this study is aimed to illustrate 1) the role of tau hyperphosphorylation in RGCs degeneration in the early phase of DR; 2) the role and relationship of 14-3-3ζ, CDK5 and GSK3β in tau hyperphosphorylation for RGCs degeneration in the early stage of DR; 3) whether 14-3-3ζ promotes tau phosphorylation by directly binding with tau and CDK5 or GSK3β. The finding of this study is expected to elucidate the underlying mechanism of RGCs degeneration at the early stage of DR and provide new targets for prevention and early treatment of DR.