Xu Xiaoyi, He Xin, Zhang Zeyan, Chen Yanyi, Li Junyu, Ma Shanshan, Huang Qiaoying, Li Mingtao
Guangdong Provincial Key Laboratory of Brain Function and Disease and Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
Guangdong Provincial Key Laboratory of Brain Function and Disease and Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
J Neurosci. 2022 Jun 1;42(22):4594-4604. doi: 10.1523/JNEUROSCI.1419-21.2022.
Understanding the pathogenesis of nigral dopaminergic neurodegeneration is critical for developing mechanism-based treatments for Parkinson's disease (PD). In the nigral dopaminergic neurons of postmortem human PD brains, we found that CREB, a well-recognized pro-survival transcription factor in neurons, was inactivated by dephosphorylation at Ser133. CREB dephosphorylation correlated with decreased expression of NURR1, one of its target genes crucial for dopaminergic neuron survival, confirming that CREB function was impaired in nigral dopaminergic neurons in PD. An MPTP mouse model was used to further elucidate the mechanism underlying CREB dephosphorylation. Protein phosphatase 1γ (PP1γ), which dephosphorylates CREB, was constitutively associated with histone deacetylase 1 (HDAC1). HDAC1 promotes CREB Ser133 dephosphorylation via a stable interaction with PP1γ. We found that CREB interacted with the HDAC1/PP1γ complex during dopaminergic neurodegeneration. Importantly, increased CREB/HDAC1 interaction occurred in the nigral dopaminergic neurons of PD patients as demonstrated using a proximity ligation assay. Disrupting CREB/HDAC1 interaction via either overexpression of GAL4 M1, a CREB mutant, or administration of trichostatin A, a pan-HDAC inhibitor, restored the expression levels of phospho-CREB (Ser133) and NURR1, and protected nigral dopaminergic neurons in the MPTP-treated mouse brain. Collectively, our results demonstrated that HDAC1/PP1γ-mediated CREB inactivation contributed to dopaminergic neuronal degeneration. Disruption of CREB/HDAC1 interaction has the potential to be a new approach for PD therapy. Parkinson's disease (PD) is the most common movement disorder attributed to the progressive loss of dopaminergic neurons in the substantia nigra. Understanding the pathogenesis of nigral dopaminergic neurodegeneration is critical for developing mechanism-based treatments for PD. We found in nigral dopaminergic neurons of postmortem human PD brains that CREB, a well-recognized pro-survival transcription factor in neurons, was inactivated by dephosphorylation at Ser133. HDAC1, constitutively associated with PP1γ, interacted with CREB to mediate its dephosphorylation during dopaminergic neurodegeneration. Disrupting CREB/HDAC1 interaction restored CREB activity and protected nigral dopaminergic neurons in the MPTP mouse brains. This work suggests that disruption of the CREB/HDAC1 interaction to restore CREB activity may be a potential therapeutic approach in PD.
了解黑质多巴胺能神经元变性的发病机制对于开发基于机制的帕金森病（PD）治疗方法至关重要。在帕金森病患者死后大脑的黑质多巴胺能神经元中，我们发现，CREB（一种在神经元中广为人知的促存活转录因子）在丝氨酸133位点发生去磷酸化而失活。CREB去磷酸化与NURR1（其对多巴胺能神经元存活至关重要的靶基因之一）表达降低相关，证实帕金森病中黑质多巴胺能神经元的CREB功能受损。使用MPTP小鼠模型进一步阐明CREB去磷酸化的潜在机制。使CREB去磷酸化的蛋白磷酸酶1γ（PP1γ）与组蛋白去乙酰化酶1（HDAC1）持续结合。HDAC1通过与PP1γ的稳定相互作用促进CREB丝氨酸133位点去磷酸化。我们发现在多巴胺能神经元变性过程中CREB与HDAC1/PP1γ复合物相互作用。重要的是，使用邻近连接分析证明，帕金森病患者黑质多巴胺能神经元中CREB/HDAC1相互作用增强。通过过表达CREB突变体GAL4 M1或给予泛HDAC抑制剂曲古抑菌素A破坏CREB/HDAC1相互作用，可恢复磷酸化CREB（丝氨酸133）和NURR1的表达水平，并保护MPTP处理的小鼠脑中的黑质多巴胺能神经元。总体而言，我们的结果表明HDAC1/PP1γ介导的CREB失活导致多巴胺能神经元变性。破坏CREB/HDAC1相互作用有可能成为帕金森病治疗的新方法。帕金森病（PD）是最常见的运动障碍，归因于黑质中多巴胺能神经元的进行性丧失。了解黑质多巴胺能神经元变性的发病机制对于开发基于机制的帕金森病治疗方法至关重要。我们在帕金森病患者死后大脑的黑质多巴胺能神经元中发现，CREB（一种在神经元中广为人知的促存活转录因子）在丝氨酸133位点发生去磷酸化而失活。与PP1γ持续结合的HDAC1在多巴胺能神经元变性过程中与CREB相互作用以介导其去磷酸化。破坏CREB/HDAC1相互作用可恢复CREB活性并保护MPTP小鼠脑中的黑质多巴胺能神经元。这项工作表明破坏CREB/HDAC相互作用以恢复CREB活性可能是帕金森病的一种潜在治疗方法。
