Chen Jiehui, Liu Yong, Zhou Keru, Zhang Wei, Wen Bin, Xu Kai, Liu Yazhou, Chen Ling, Huang Yue, He Benhong, Hang Weijian, Chen Juan
Department of Biochemistry and Molecular Biology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Neonatal Intensive Care Unit, Department of Pediatric, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Biofactors. 2023 Jan;49(1):173-184. doi: 10.1002/biof.1884. Epub 2022 Sep 7.
Diabetic encephalopathy (DE) is a common complication of type 2 diabetes (T2D), especially in those patients with long T2D history. Persistent high glucose (HG) stimulation leads to neuron damage and manifests like Alzheimer's disease's pathological features such as neurofilament tangle. However, the precise mechanism of high-glucose-induced tau hyperphosphorylation is not fully revealed. We here gave evidence that Disrupted in schizophrenia 1 protein (DISC1) could interact with glycogen synthase kinase 3β (GSK3β) and inhibit its activity to prevent tau hyperphosphorylation. By using DB/DB mice as animal model and HG-treated N2a cell as cell model, we found that DISC1 was downregulated both in vivo and in vitro, complicated with Tau hyperphosphorylation and GSK3β activation. Further, we identified DISC1 interacted with GSK3β by its 198th-237th amino acid residues. Overexpression of full length DISC1 but not mutated DISC1 lacking this domain could prevent HG induced tau hyperphosphorylation. Taken together, our work revealed DISC1 could be an important negative modulators of tau phosphorylation, and suggested that preservation of DISC1 could prevent HG induced neuron damage.
糖尿病性脑病（DE）是2型糖尿病（T2D）的常见并发症，尤其是在那些有较长T2D病史的患者中。持续的高血糖（HG）刺激会导致神经元损伤，并表现出如阿尔茨海默病的病理特征，如神经丝缠结。然而，高糖诱导tau蛋白过度磷酸化的确切机制尚未完全阐明。我们在此提供证据表明，精神分裂症1蛋白（DISC1）可与糖原合酶激酶3β（GSK3β）相互作用并抑制其活性，以防止tau蛋白过度磷酸化。通过使用DB/DB小鼠作为动物模型和HG处理的N2a细胞作为细胞模型，我们发现DISC1在体内和体外均下调，伴有Tau蛋白过度磷酸化和GSK3β激活。此外，我们确定DISC1通过其第198至237个氨基酸残基与GSK3β相互作用。全长DISC1的过表达而非缺乏该结构域的突变DISC1可以防止HG诱导的tau蛋白过度磷酸化。综上所述，我们的研究表明DISC1可能是tau蛋白磷酸化的重要负性调节因子，并提示维持DISC1水平可预防HG诱导的神经元损伤。
