Neurology Department, Jintan Hospital Affiliated to Jiangsu University, Changzhou, 213200, Jiangsu, China.
School of Pharmacy, Jiangsu University, Zhenjiang, 212013, Jiangsu, China.
Eur J Pharmacol. 2021 Sep 15;907:174202. doi: 10.1016/j.ejphar.2021.174202. Epub 2021 May 26.
Parkinson's disease (PD) is a common neurological disorder worldwide, characterized by loss of dopaminergic neurons and decrease of dopamine content. Mitochondria plays an important role in the development of PD. Adenosine 5'-monophosphate-activated protein kinase (AMPK), glycogen synthase kinase 3 (GSK-3β) and protein phosphatase 2A (PP2A) are all key proteins that regulate mitochondrial metabolism and apoptosis, and they are involved in a variety of neurodegenerative diseases. Here, we aimed to explore the involvement of mitochondrial dysfunction and apoptosis in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP)-induced PD mice and MPP iodide-induced PC12 cells. MPTP-induced mice were subjected to behavioral testing to assess PD-like behaviors. Various molecular biological techniques including ELISA, Western blot, TUNEL assay, flow cytometry, and the important instruments Seahorse XF24 Extracellular and high performance liquid chromatography (HPLC), were used to identify the underlying molecular events of mitochondria. Treatment with the AMPK activator GSK621 dramatically ameliorated PD by increasing the levels of dopamine and rescuing the loss of dopaminergic neurons, which is dependent on the mitochondrial pathway. Moreover, regulation of AMPK/GSK-3β/PP2A pathway-related proteins by GSK621 was partially inhibited the development of PD, suggesting a negative feedback loop exists between AMPK action and mitochondrial dysfunction-mediated apoptosis. Our data preliminarily indicated that mitochondrial dysfunction and apoptosis in the pathogenesis of PD might be mediated by AMPK/GSK-3β/PP2A pathway action, which might be a promising new option for future therapy of PD.
帕金森病（PD）是一种常见的全球神经系统疾病，其特征是多巴胺能神经元丧失和多巴胺含量减少。线粒体在 PD 的发展中起着重要作用。腺苷 5'-单磷酸激活蛋白激酶（AMPK）、糖原合酶激酶 3（GSK-3β）和蛋白磷酸酶 2A（PP2A）都是调节线粒体代谢和细胞凋亡的关键蛋白，它们参与多种神经退行性疾病。在这里，我们旨在探讨线粒体功能障碍和细胞凋亡在 1-甲基-4-苯基-1,2,3,6-四氢吡啶盐酸盐（MPTP）诱导的 PD 小鼠和 MPP 碘化物诱导的 PC12 细胞中的作用。MPTP 诱导的小鼠进行行为测试以评估类似 PD 的行为。各种分子生物学技术，包括 ELISA、Western blot、TUNEL 测定、流式细胞术和重要仪器 Seahorse XF24 细胞外和高效液相色谱（HPLC），用于鉴定线粒体的潜在分子事件。用 AMPK 激活剂 GSK621 处理可通过增加多巴胺水平和挽救多巴胺能神经元的丧失来显著改善 PD，这依赖于线粒体途径。此外，GSK621 对 AMPK/GSK-3β/PP2A 通路相关蛋白的调节部分抑制了 PD 的发展，这表明 AMPK 作用和线粒体功能障碍介导的细胞凋亡之间存在负反馈环。我们的数据初步表明，线粒体功能障碍和细胞凋亡可能是通过 AMPK/GSK-3β/PP2A 通路作用介导的 PD 发病机制，这可能是未来 PD 治疗的一个有希望的新选择。
