DISC1 inhibits GSK3β activity to prevent tau hyperphosphorylation under diabetic encephalopathy
DISC1 inhibits GSK3β activity to prevent tau hyperphosphorylation under diabetic encephalopathy
复制标题
DISC1 抑制 GSK3β 活性以防止糖尿病脑病下 tau 过度磷酸化。
DOI：
10.1002/biof.1884
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发表时间：
2022-09-07
期刊：
影响因子：
6
通讯作者：
Chen, Juan
中科院分区：
文献类型：
--
作者：
Chen, Jiehui;Liu, Yong;Chen, Juan
糖尿病脑病（diabetic encephalopathy，DE）是2型糖尿病（type 2 diabetes，T2 D）的常见并发症，尤其是有较长病史的患者。持续的高葡萄糖（HG）刺激导致神经元损伤，并表现出类似阿尔茨海默病的病理特征，如神经丝缠结。然而，高糖诱导的tau蛋白过度磷酸化的确切机制尚未完全揭示。我们在这里提供的证据表明，精神分裂症1蛋白（DISC 1）可以与糖原合成酶激酶3 β（GSK 3 β）相互作用，并抑制其活性，以防止tau蛋白过度磷酸化。以DB/DB小鼠为动物模型，HG处理的N2 a细胞为细胞模型，发现DISC 1在体内外均下调，并伴有Tau蛋白过度磷酸化和GSK 3 p激活。此外，我们确定了DISC 1通过其第198 - 237位氨基酸残基与GSK 3 β相互作用。过表达全长DISC 1而不是缺乏该结构域的突变DISC 1可以防止HG诱导的tau过度磷酸化。综上所述，我们的工作揭示了DISC 1可能是tau磷酸化的重要负性调节剂，并表明DISC 1的保存可以防止HG诱导的神经元损伤。
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 3 beta (GSK3 beta) 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 GSK3p activation. Further, we identified DISC1 interacted with GSK3p 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.