Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, 100069, China.
Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, 100069, China.
Neurochem Int. 2022 Oct;159:105389. doi: 10.1016/j.neuint.2022.105389. Epub 2022 Jul 7.
There are currently no treatments to delay or prevent Parkinson's disease (PD), and protective treatments require early administration. Targeting axonal degeneration in early PD could have an important clinical effect; however, the underlying molecular mechanisms controlling axonal degeneration in PD are not fully understood. Here, we studied the role of Wnt/β-catenin signaling in axonal degeneration induced by 6-hydroxydopamine (6-OHDA) or overexpression of alpha-synuclein (α-Syn) in vitro and in vivo. We found that the levels of both β-catenin and p-S9-glycogen synthase kinase-3β (GSK-3β) increased and the levels of phosphorylated β-catenin (p-β-catenin) decreased during 6-OHDA-induced axonal degeneration and that the inhibitors of the Wnt/β-catenin pathway IWR-1 and Dickkopf-1 (DKK-1) attenuated the degenerative process in primary neurons in vitro. Furthermore, IWR-1 enhanced the increase of LC3-II levels and the decrease of p62 triggered by 6-OHDA treatment, whereas the autophagy inhibitor 3-Methyladenine (3-MA) alleviated the protective effect of IWR-1 on axons in vitro. Consistent with the in vitro findings, both β-catenin and p-S9-GSK-3β were upregulated in a 6-OHDA-induced rat PD model, and blocking the Wnt/β-catenin pathway with DKK-1 attenuated the degeneration of dopaminergic axons at an early time point in vivo. The protective effect of inhibition of Wnt/β-catenin signaling was further confirmed in an α-Syn overexpression-induced animal models of PD. Taken together, these data indicate that the Wnt/β-catenin pathway is involved axonal degeneration in PD, and suggest that Wnt/β-catenin pathway inhibitors have the therapeutic potential for the prevention of PD.
目前尚无治疗方法可以延缓或预防帕金森病（PD），而保护性治疗需要早期给药。针对早期 PD 中的轴突变性可能具有重要的临床效果；然而，控制 PD 中轴突变性的潜在分子机制尚未完全阐明。在这里，我们研究了 Wnt/β-catenin 信号通路在 6-羟多巴胺（6-OHDA）诱导的轴突变性或α-突触核蛋白（α-Syn）过表达体外和体内的作用。我们发现，6-OHDA 诱导的轴突变性过程中β-catenin 和 p-S9-糖原合酶激酶-3β（GSK-3β）水平升高，磷酸化β-catenin（p-β-catenin）水平降低，Wnt/β-catenin 通路抑制剂 IWR-1 和 Dickkopf-1（DKK-1）可减轻体外原代神经元的退行性过程。此外，IWR-1 增强了 6-OHDA 处理后 LC3-II 水平的增加和 p62 的减少，而自噬抑制剂 3-甲基腺嘌呤（3-MA）减轻了 IWR-1 在体外对轴突的保护作用。与体外研究结果一致，6-OHDA 诱导的 PD 大鼠模型中β-catenin 和 p-S9-GSK-3β 均上调，用 DKK-1 阻断 Wnt/β-catenin 通路可减轻体内早期多巴胺能轴突的变性。在α-Syn 过表达诱导的 PD 动物模型中进一步证实了抑制 Wnt/β-catenin 信号的保护作用。综上所述，这些数据表明 Wnt/β-catenin 通路参与 PD 中的轴突变性，并表明 Wnt/β-catenin 通路抑制剂具有预防 PD 的治疗潜力。
