Department of Anatomy, Histology and Embryology, Health Science Center, Peking University, Beijing, China.
Neuroscience Research Institute, Peking University, Beijing, China.
Cell Death Differ. 2021 Aug;28(8):2517-2535. doi: 10.1038/s41418-021-00767-2. Epub 2021 Mar 24.
The pathogenesis of Parkinson's disease (PD) remains unclear, and there is no disease-modifying agent for PD. Withaferin A (WA), a naturally occurring compound, has emerged as a neuroprotective agent. However, the mechanisms by which WA is neuroprotective in PD are unknown. Here we show that WA protected against loss of dopaminergic neurons, neuroinflammation, and motor deficits in MPTP-induced PD mouse models. Whole-genome deep sequencing analysis combined with Meta-analysis of human PD studies reveal that DJ1, Nrf2, and STING in substantia nigra pars compacta (SNc) are linked to anti-PD effect of WA. We found that WA activated DJ1 and Nrf2, and suppressed STING within SNc; and overexpression of STING in SNc dampened the effect of WA. Using genetically modified mice (DJ1-KO, Nrf2-KO, STING and STING-KO) and immunolabeling technique, we identified that WA targeted DJ1-Nrf2-STING pathway in dopaminergic neurons; and we demonstrate that STING might be an important factor in PD pathogenesis. In addition, WA alleviated accumulation of phosphorylated α-synuclein (p-α-syn) and insoluble α-syn within SNc in adeno-associated virus (AAV)-mediated human α-syn overexpression PD model. Our comparative analysis on whole-genome transcriptome profiles suggests that STING might be a key target of WA and amantadine in PD treatment. This study highlights a multifaceted role for WA in neuroprotection, and suggests that WA can be a potential candidate for treatment of PD.
帕金森病（PD）的发病机制尚不清楚，也没有针对 PD 的疾病修饰药物。辣木素 A（WA）是一种天然存在的化合物，已成为一种神经保护剂。然而，WA 在 PD 中具有神经保护作用的机制尚不清楚。在这里，我们表明 WA 可防止 MPTP 诱导的 PD 小鼠模型中多巴胺能神经元的丧失、神经炎症和运动功能障碍。全基因组深度测序分析结合人类 PD 研究的 Meta 分析表明，黑质致密部（SNc）中的 DJ1、Nrf2 和 STING 与 WA 的抗 PD 作用有关。我们发现 WA 激活了 DJ1 和 Nrf2，并抑制了 SNc 中的 STING；而 SNc 中 STING 的过表达削弱了 WA 的作用。使用基因修饰小鼠（DJ1-KO、Nrf2-KO、STING 和 STING-KO）和免疫标记技术，我们确定了 WA 在多巴胺能神经元中靶向 DJ1-Nrf2-STING 通路；并证明 STING 可能是 PD 发病机制中的一个重要因素。此外，WA 减轻了腺相关病毒（AAV）介导的人α-突触核蛋白（α-syn）过表达 PD 模型中 SNc 内磷酸化α-突触核蛋白（p-α-syn）和不溶性α-syn 的积累。我们对全基因组转录组谱的比较分析表明，STING 可能是 WA 和金刚烷胺治疗 PD 的关键靶点。这项研究强调了 WA 在神经保护中的多方面作用，并表明 WA 可能是治疗 PD 的潜在候选药物。
