Department of Neurology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan.
Department of Neurology, College of Medicine, School of Medicine, Taipei Medical University, Taipei City 110, Taiwan.
Cells. 2020 Mar 17;9(3):740. doi: 10.3390/cells9030740.
Insulin resistance (IR), considered a hallmark of diabetes at the cellular level, is implicated in pre-diabetes, results in type 2 diabetes, and negatively affects mitochondrial function. Diabetes is increasingly associated with enhanced risk of developing Parkinson's disease (PD); however, the underlying mechanism remains unclear. This study investigated the probable culpability of IR in the pathogenesis of PD. Using MitoPark mice in vivo models, diabetes was induced by a high-fat diet in the in vivo models, and IR was induced by protracted pulse-stimulation with 100 nM insulin treatment of neuronal cells, in vitro to determine the molecular mechanism(s) underlying altered cellular functions in PD, including mitochondrial dysfunction and α-synuclein (SNCA) aberrant expression. We observed increased SNCA expression in the dopaminergic (DA) neurons of both the wild-type and diabetic MitoPark mice, coupled with enhanced degeneration of DA neurons in the diabetic MitoPark mice. Ex vivo, in differentiated human DA neurons, IR was associated with increased SNCA and reactive oxygen species (ROS) levels, as well as mitochondrial depolarization. Moreover, we demonstrated concomitant hyperactivation of polo-like kinase-2 (PLK2), and upregulated p-SNCA (Ser129) and proteinase K-resistant SNCA proteins level in IR SH-SY5Y cells, however the inhibition of PLK2 reversed IR-related increases in phosphorylated and total SNCA. Similarly, the overexpression of peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC)-1α suppressed ROS production, repressed PLK2 hyperactivity, and resulted in downregulation of total and Ser129-phosphorylated SNCA in the IR SH-SY5Y cells. These findings demonstrate that IR-associated diabetes promotes the development and progression of PD through PLK2-mediated mitochondrial dysfunction, upregulated ROS production, and enhanced SNCA signaling, suggesting the therapeutic targetability of PLK2 and/or SNCA as potential novel disease-modifying strategies in patients with PD.
胰岛素抵抗（IR）被认为是细胞水平糖尿病的标志，与糖尿病前期、2 型糖尿病有关，并对线粒体功能产生负面影响。糖尿病与帕金森病（PD）风险增加密切相关；然而，其潜在机制尚不清楚。本研究探讨了 IR 在 PD 发病机制中的可能作用。 本研究使用 MitoPark 小鼠体内模型，通过高脂肪饮食在体内模型中诱导糖尿病，通过延长用 100 nM 胰岛素脉冲刺激神经元细胞诱导 IR，在体外确定改变 PD 中细胞功能的分子机制，包括线粒体功能障碍和α-突触核蛋白（SNCA）异常表达。 我们观察到野生型和糖尿病 MitoPark 小鼠的多巴胺能（DA）神经元中 SNCA 表达增加，并且糖尿病 MitoPark 小鼠的 DA 神经元退化增强。在体外，在分化的人 DA 神经元中，IR 与 SNCA 和活性氧（ROS）水平升高以及线粒体去极化有关。此外，我们在 IR SH-SY5Y 细胞中证明了 Polo 样激酶-2（PLK2）的协同过度激活，以及 p-SNCA（Ser129）和蛋白水解酶抗性 SNCA 蛋白水平升高，而 PLK2 的抑制作用逆转了 IR 相关的磷酸化和总 SNCA 增加。同样，过表达过氧化物酶体增殖物激活受体-γ共激活因子 1-α（PGC）-1α 可抑制 ROS 产生，抑制 PLK2 过度激活，并导致 IR SH-SY5Y 细胞中总和 Ser129 磷酸化 SNCA 下调。 这些发现表明，与 IR 相关的糖尿病通过 PLK2 介导的线粒体功能障碍、ROS 产生增加和增强的 SNCA 信号转导促进 PD 的发展和进展，表明 PLK2 和/或 SNCA 作为 PD 患者潜在的新型疾病修饰策略具有治疗靶向性。
