Enhancing Beta-Catenin Activity via GSK3beta Inhibition Protects PC12 Cells against Rotenone Toxicity through Nurr1 Induction.
Enhancing Beta-Catenin Activity via GSK3beta Inhibition Protects PC12 Cells against Rotenone Toxicity through Nurr1 Induction.
复制标题
通过 GSK3beta 抑制增强 β-连环蛋白活性，通过 Nurr1 诱导保护 PC12 细胞免受鱼藤酮毒性
DOI：
10.1371/journal.pone.0152931
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Xu P
中科院分区：
文献类型：
--
作者：
Zhang L;Cen L;Qu S;Wei L;Mo M;Feng J;Sun C;Xiao Y;Luo Q;Li S;Yang X;Xu P
帕金森病（Parkinson's disease，PD）是一种以黑质多巴胺（dopaminergic，DA）能神经元进行性变性为特征的疾病。越来越多的证据表明，Wnt/β-catenin通路和孤儿核受体Nurr 1在中脑DA能神经元的存活和功能维持中起着重要作用，GSK-3β拮抗剂LiCl和SB 216763在实验上激活了Wnt/β-catenin通路。然而，Wnt/β-catenin与Nurr 1之间的相互作用机制尚不清楚。本研究采用细胞生物学方法研究了Wnt/β-catenin在体外PC 12细胞变性过程中的作用及其与Nurr 1的相互作用。我们的数据表明，鱼藤酮抑制PC 12细胞活力，但GSK-3β拮抗剂LiCl或SB 216763减弱。Wnt/β-catenin信号通路活性在鱼藤酮作用下呈浓度依赖性下调。siRNA干扰β-catenin后，LiCl或SB 216763均不能保护鱼藤酮引起的PC 12细胞凋亡。我们的数据证实了LiCl或SB 216763激活的Wnt/β-catenin信号通路分别使Nurr 1的表达增加到对照的2.75 ± 0.55和4.06 ± 0.41倍，并通过免疫共沉淀分析鉴定了β-catenin与Nurr 1的相互作用。结论：Wnt/β-catenin和Nurr 1是DA能神经元存活的关键因素，Wnt/β-catenin通路的激活部分通过与Nurr 1的协同作用对DA能神经元发挥保护作用。这一发现可能为帕金森病的潜在治疗提供了线索。
Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic (DA) neurons in the substantial nigra pars compacta. Increasing evidence showed that Wnt/β-catenin pathway and the orphan nuclear receptor Nurr1 play crucial roles in the survival and functional maintenance of DA neurons in the midbrain and GSK-3β antagonists LiCl and SB216763 were used to activate Wnt/β-catenin pathway experimentally. However, the detail mechanism underlying the neuroprotection against apoptosis on DA neuron is still unclear and the interaction between Wnt/β-catenin and Nurr1 remains undisclosed. In this study, using cell biological assay we investigated the function of Wnt/β-catenin and its crosstalk with Nurr1 on the course of PC12 cell degeneration in vitro. Our data showed that PC12 cell viability was inhibited by rotenone, but attenuated by GSK-3β antagonists LiCl or SB216763. The activity of Wnt/β-catenin pathway was deregulated on exposure of rotenone in a concentration-dependent manner. After the interference of β-catenin with siRNA, LiCl or SB216763 failed to protect PC12 cells from apoptosis by the rotenone toxicity. Our data confirmed that Wnt/β-catenin signaling activated by LiCl or SB216763 enhanced Nurr1 expression to 2.75 ± 0.55 and 4.06 ± 0.41 folds respectively compared with control detected by real-time PCR and the interaction of β-catenin with Nurr1 was identified by co-immunoprecipitate analysis. In conclusion, the data suggested that Wnt/β-catenin and Nurr1 are crucial factors in the survival of DA neurons, and the activation of Wnt/β-catenin pathway exerts protective effects on DA neurons partly by mean of a co-active pattern with Nurr1. This finding may shed a light on the potential treatment of Parkinson disease.