Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao, China.
School of Basic Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, China.
Am J Physiol Endocrinol Metab. 2020 Oct 1;319(4):E734-E743. doi: 10.1152/ajpendo.00071.2020. Epub 2020 Aug 31.
Autophagy dysfunctions are involved in the pathogenesis of Parkinson's disease (PD). In the present study, we aimed to evaluate the involvement of G protein-coupled estrogen receptor (GPER) in the inhibitory effect of insulin-like growth factor-1 (IGF-1) against excessive autophagy in PD animal and cellular models. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment significantly induced mouse movement disorder and decreased the protein level of tyrosine hydroxylase (TH) in the substantia nigra (SN) and dopamine (DA) content in striatum. Along with the dopamine neuron injury, we observed significant upregulations of microtubule-associated light chain-3 II (LC3-II) and α-synuclein as well as a downregulation of P62 in MPTP-treated mice. These changes could be restored by IGF-1 pretreatment. Cotreatment with IGF-1R antagonist JB-1 or GPER antagonist G15 could block the neuroprotective effects of IGF-1. 1-Methy-4-phenylpyridinium (MPP) treatment could also excessively activate autophagy along with the reduction of cell viability in SH-SY5Y cells. IGF-1 could inhibit the neurotoxicity through promoting the phosphorylation of Akt and mammalian target of rapamycin (mTOR), which could also be antagonized by JB-1 or G15. These data suggest that IGF-1 inhibits MPTP/MPP-induced autophagy on dopaminergic neurons through the IGF-1R/PI3K-Akt-mTOR pathway and GPER.
自噬功能障碍与帕金森病（PD）的发病机制有关。在本研究中，我们旨在评估 G 蛋白偶联雌激素受体（GPER）在胰岛素样生长因子-1（IGF-1）抑制 PD 动物和细胞模型中过度自噬中的作用。1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理显著诱导小鼠运动障碍，并降低黑质（SN）中酪氨酸羟化酶（TH）的蛋白水平和纹状体中多巴胺（DA）的含量。随着多巴胺神经元损伤，我们观察到微管相关轻链-3 II（LC3-II）和α-突触核蛋白的显著上调以及 MPTP 处理小鼠中 P62 的下调。IGF-1 预处理可以恢复这些变化。用 IGF-1R 拮抗剂 JB-1 或 GPER 拮抗剂 G15 共处理可阻断 IGF-1 的神经保护作用。1-甲基-4-苯基吡啶（MPP）处理也可过度激活自噬，同时降低 SH-SY5Y 细胞的细胞活力。IGF-1 可通过促进 Akt 和雷帕霉素靶蛋白（mTOR）的磷酸化来抑制神经毒性，这也可被 JB-1 或 G15 拮抗。这些数据表明，IGF-1 通过 IGF-1R/PI3K-Akt-mTOR 途径和 GPER 抑制 MPTP/MPP 诱导的多巴胺能神经元自噬。
