Parkinson's disease (PD), the second most common chronic neurodegenerative disorder, broadly remains incurable. Both genetic susceptibility and exposure to deleterious environmental stimuli contribute to dopaminergic neuron degeneration in the substantia nigra. Hence, reagents that can ameliorate the phenotypes rendered by genetic or environmental factors should be considered in PD therapy. In this study, we found that polydatin (Pol), a natural compound extracted from grapes and red wines, significantly attenuated rotenone- (Rot) or Parkin deficiency-induced mitochondrial dysfunction and cell death in SH-SY5Y, a human dopaminergic neuronal cell line. We showed that Pol significantly attenuated the Rot-induced decrease in cell viability, mitochondrial membrane potential (MMP), and Sirt 1 expression and increase in cell death, reactive oxygen species (ROS) and DJ1 expression. Rot resulted in a decrease in mTOR/Ulk-involved autophagy and an increase in PGC1β/mfn2-involved mitochondrial fusion, which was inhibited by Pol. We further demonstrated that the protective effects of Pol are partially blocked when autophagy-related gene 5 (Atg5) is genetically inactivated, suggesting that Pol-mediated neuroprotection requires Atg5. Moreover, Pol rescued Parkin knockdown-induced oxidative stress, mitochondrial dysfunction, autophagy impairment, and mitochondrial fusion enhancement. Interestingly, Pol treatment could also rescue the mitochondrial morphological abnormality and motorial dysfunction of a Drosophila PD model induced by Parkin deficiency. Thus, Pol could represent a useful therapeutic strategy as a disease-modifier in PD by decreasing oxidative stress and regulating autophagic processes and mitochondrial fusion.

中文翻译：

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Polydatin通过促进Atg5介导但不依赖于Parkin的自噬保护帕金森病模型中的SH-SY5Y。

帕金森氏病（PD）是第二种最常见的慢性神经退行性疾病，目前仍可治愈。遗传易感性和暴露于有害环境刺激均会导致黑质中多巴胺能神经元变性。因此，在PD治疗中应考虑可改善遗传或环境因素导致的表型的试剂。在这项研究中，我们发现从葡萄和红酒中提取的天然化合物多拉丁素（Pol）可显着减轻人多巴胺能神经元细胞SH-SY5Y中鱼藤酮（Rot）或帕金缺乏症引起的线粒体功能障碍和细胞死亡。 。我们发现，Pol显着减轻了Rot诱导的细胞活力，线粒体膜电位（MMP）和Sirt 1表达的降低以及细胞死亡的增加，活性氧（ROS）和DJ1表达。腐烂导致mTOR / Ulk参与的自噬减少，PGC1β/ mfn2参与的线粒体融合增加，这被Pol抑制。我们进一步证明，当自噬相关基因5（Atg5）被基因灭活时，Pol的保护作用被部分阻断，这表明Pol介导的神经保护作用需要Atg5。此外，Pol挽救了Parkin敲低引起的氧化应激，线粒体功能障碍，自噬功能障碍和线粒体融合增强。有趣的是，Pol治疗还可以挽救帕金缺乏引起的果蝇PD模型的线粒体形态异常和运动功能障碍。从而，