Nurr1 downregulation is caused by CREB inactivation in a Parkinson's disease mouse model
Nurr1 downregulation is caused by CREB inactivation in a Parkinson's disease mouse model
复制标题
帕金森病小鼠模型中 Nurr1 下调是由 CREB 失活引起的
DOI：
10.1016/j.neulet.2021.136045
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发表时间：
2021
影响因子：
2.5
通讯作者：
Huang Qiaoying
中科院分区：
文献类型：
--
作者：
Xu Xiaoyi;He Xin;Ma Shanshan;Li Mingtao;Huang Qiaoying
帕金森病（Parkinson's disease，PD）是一种以黑质（substantia nigra，SN）多巴胺能神经元缺失为特征的进行性神经退行性疾病。Nurr 1（NR 4A 2）是维持中脑多巴胺能神经元所必需的核受体，在PD患者和动物模型中转录下调，并被认为是PD神经保护的有希望的治疗靶点。然而，多巴胺能变性过程中Nurr 1下调的机制尚未完全阐明。在这里，我们报告，促生存转录因子CREB是组成性结合到theNurr 1启动子在小鼠SN。CREB失活Ser 133的去磷酸化与Nurr 1下调并行发生在MPTP小鼠PD模型。强制表达VP 16-CREB，一种组成型活性突变体，拯救了Nurr 1的表达，并在MPTP中毒小鼠中显示出显著的神经保护作用。总的来说，我们的研究结果表明，Nurr 1下调MPTP诱导的PD小鼠模型是由CREB失活，这可能提供了一个新的目标，在PD的神经保护治疗。
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Nurr1 (NR4A2), a nuclear receptor essential for the maintenance of midbrain dopaminergic neurons, is transcriptionally downregulated in both patients with PD and animal models and has been considered as a promising therapeutic target for neuroprotection in PD. However, the mechanism underlying Nurr1 downregulation during dopaminergic degeneration has not been fully elucidated. Here, we report that the pro-survival transcription factor CREB is constitutively bound to theNurr1promoter in the mouse SN. CREB inactivation by dephosphorylation at Ser133 occurred in parallel with Nurr1 downregulation in the MPTP mouse model of PD. Forced expression of VP16-CREB, a constitutively active mutant, rescued Nurr1 expression and showed prominent neuroprotection in MPTP-intoxicated mice. Collectively, our results demonstrate that Nurr1 downregulation in the MPTP-induced PD mouse model is caused by CREB inactivation, which may provide a new target for neuroprotective therapy in PD.