Zhang Can-Tang, Qin Deng-Li, Cao Xia-Yin, Kan Jia-Shuo, Huang Xin-Xing, Gao Dian-Shuai, Gao Jin
Department of Respiratory and Critical Care, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
Department of Neurobiology and Cell Biology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
iScience. 2023 Jun 7;26(7):107049. doi: 10.1016/j.isci.2023.107049. eCollection 2023 Jul 21.
Parkinson's disease (PD) is a neurodegenerative disease characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). We recently reported that Six2 could reverse the degeneration of DA neurons in a dephosphorylation state. Here we further identified that Eya1 was the phosphatase of Six2 that could dephosphorylate the tyrosine 129 (Y129) site by forming a complex with Six2 in damaged DA cells. Dephosphorylated Six2 then translocates from the cytoplasm to the nucleus. Using ChIP-qPCR and dual luciferase assay, we found that dephosphorylated Six2 down-regulates TEA domain1 (Tead1) expression, thus inhibiting 6-hydroxydopamine (6-OHDA)-induced apoptosis in DA cells. Furthermore, we showed Six2Y129F/Tead1 signaling could protect against the loss of SNpc tyrosine hydroxylase-positive (TH) cells and improve motor function in PD model rats. Our results demonstrate a dephosphorylation-dependent mechanism of Six2 that restores the degeneration of DA neurons, which could represent a potential therapeutic target for PD.
帕金森病（PD）是一种神经退行性疾病，其特征是黑质致密部（SNpc）中多巴胺能（DA）神经元选择性丧失。我们最近报道，Six2可以在去磷酸化状态下逆转DA神经元的退化。在这里，我们进一步确定Eya1是Six2的磷酸酶，它可以通过在受损的DA细胞中与Six2形成复合物来使酪氨酸129（Y129）位点去磷酸化。去磷酸化的Six2随后从细胞质转移到细胞核。使用染色质免疫沉淀定量聚合酶链反应（ChIP-qPCR）和双荧光素酶测定，我们发现去磷酸化的Six2下调TEA结构域1（Tead1）的表达，从而抑制6-羟基多巴胺（6-OHDA）诱导的DA细胞凋亡。此外，我们表明Six2Y129F/Tead1信号通路可以防止SNpc酪氨酸羟化酶阳性（TH）细胞的丧失，并改善PD模型大鼠的运动功能。我们的结果证明了Six2的一种依赖去磷酸化的机制，该机制可恢复DA神经元的退化，这可能是PD的一个潜在治疗靶点。
