Downregulation of DEC1 contributes to the neurotoxicity induced by MPP+ by suppressing PI3K/Akt/GSK3 pathway
Downregulation of DEC1 contributes to the neurotoxicity induced by MPP+ by suppressing PI3K/Akt/GSK3 pathway
复制标题
DEC1 的下调通过抑制 PI3K/Akt/GSK3 通路导致 MPP 诱导的神经毒性
DOI：
10.1111/cns.12717
复制
发表时间：
2017
影响因子：
5.5
通讯作者：
Yang Jian
中科院分区：
文献类型：
--
作者：
Zhu Zhu;Wang Yu-Wen;Ge Ding-Hao;Lu Ming;Liu Wei;Xiong Jing;Hu Gang;Li Xiao-Ping;Yang Jian
目的分化胚胎软骨细胞基因1(DEC1)参与神经元的分化和发育。本研究旨在探讨DEC1在1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPP+)诱导的帕金森病模型中的作用。方法用免疫荧光法检测DEC1和酪氨酸羟化酶(TH)阳性神经元的位置。建立1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)诱导的亚急性帕金森病小鼠模型，观察DEC1在中脑的表达变化。结果共表达的DEC1和TH神经元占小鼠中脑TH神经元的80%以上。MPTP损伤组SNPC和VTA的DEC1/TH双阳性神经元减少了40.6%和28.8%。MPTP组小鼠中脑DEC1、TH和多巴胺转运体(DAT)的表达持续下降。在SY-SY5Y细胞中，MPP+显著抑制DEC1的表达，增加caspase3/caspase3和Bax/Bcl2的裂解。DEC1的过表达减轻，而DEC1的敲除加重了MPP+的细胞毒作用。同样，β-连环蛋白和PI3Kp110α(PIK3CA)在Wnt/β-连环蛋白和PI3K/Akt信号通路中起重要作用。有趣的是，PI3K/AKT信号的抑制剂LY294002加重了PI3K/AKT信号的抑制作用，而WNT/β-连环蛋白信号的激活剂LiCl2则取消了MPP+对DEC1的抑制作用。Gsk3β的磷酸化状态决定了这两条通路的相互联系。结论DEC1基因表达下调可能通过抑制PI3K/Akt/Gsk3β通路参与MPP+诱导的神经毒性作用。
AimDifferentiated embryonic chondrocyte gene 1 (DEC1) is involved in the neuronal differentiation and development. The aim of this study is to investigate the role of DEC1 in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPP+)‐induced PD model.MethodsThe location of DEC1 and tyrosine hydroxylase (TH)‐positive neurons were detected by immunofluorescence. 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced mouse subacute model of PD was established to evaluate the change of DEC1 expression in midbrain. Then, SH‐SY5Y cells were used to investigate the role of DEC1 in MPP+‐induced neurotoxicity.ResultsWe showed that the co‐expressed DEC1 and TH neurons took up more than 80% of the expressed TH neurons in the midbrain of mice. DEC1/TH double‐positive neurons decreased by 40.6% in SNpc and 28.8% in VTA of MPTP‐injured mice. Consistently, DEC1, TH and dopamine transporter (DAT) expression decreased in the midbrain of MPTP mice. In SY‐SY5Y cells, MPP+significantly suppressed DEC1 expression and increased the cleaved caspase 3/caspase 3 and Bax/Bcl‐2. DEC1 overexpression relieved, whereas DEC1 knockdown aggravated MPP+‐induced cytotoxicity. Likewise, DEC1 overexpression and knockdown inversely regulated the expression of β‐catenin and PI3Kp110α (PIK3CA), an essential role in Wnt/β‐catenin and PI3K/Akt signaling pathways. Interestingly, LY294002, an inhibitor of PI3K/Akt signaling, aggravated, whereas LiCl, an activator of Wnt/β‐catenin signaling, abolished the reduction in DEC1 by MPP+. It is established that these two pathways are interconnected by the phosphorylation status of GSK3β. DEC1 overexpression increased but MPP+and DEC1 knockdown decreased GSK3β phosphorylation.ConclusionDownregulation of DEC1 contributes to MPP+‐induced neurotoxicity by suppressing PI3K/Akt/GSK3β pathway.