Abstract：
Post-translational modification, mitochondrial abruptions, neuroinflammation, and α-synuclein (α-Syn) aggregation are considered as major causes of Parkinson\'s disease (PD) pathogenesis. The recent literature highlights neuroimmune cross talk and the negative role of immune effector T (Teff) and positive regulation by regulatory T (Treg) cells in PD treatment. Herein, a strategy to endow Treg action paves the path for development of PD treatment. Thus, we explored the neuroprotective efficiency of the immunomodulator and PP2A (protein phosphatase 2) activator, FTY720 nanoparticles in in vivo experimental PD models. Repurposing of FTY720 for PD is known due to its protective effect by reducing PD and its camouflaged role in endowing EZH2-mediated epigenetic regulation of PD. EZH2-FOXP3 interaction is necessary for the neuroprotective Treg cell activity. Therefore, we synthesized FTY720 nanoparticles to improve FTY720 protective efficacy in an in vivo PD model to explore the PP2A mediated signaling. We confirmed the formation of FTY720NPs, and the results of the behavioral and protein expression study showed the significant neuroprotective efficiency of our nanoformulations. In the exploration of neuroprotective mechanism, several lines of evidence confirmed FTY720NPs mediated induction of PP2A/EZH2/FOXP3 signaling in the induction of Treg cells effect in in vivo PD treatment. In summary, our nanoformulations have novel potential to alleviate PD by inducing PP2A-induced epigenetic regulation-mediated neuroimmunomodulation at the clinical setup.
摘要：
翻译后修饰,线粒体破裂，神经炎症，和α-突触核蛋白（α-Syn）聚集被认为是帕金森病（PD）发病的主要原因。最近的文献强调了神经免疫串扰和免疫效应T（Teff）的负面作用以及调节性T（Treg）细胞在PD治疗中的正向调节。在这里，赋予Treg作用的策略为PD治疗的发展铺平了道路。因此，我们探索了免疫调节剂和PP2A（蛋白磷酸酶2）激活剂的神经保护效率，FTY720纳米颗粒在体内实验PD模型中的应用。已知FTY720用于PD的再利用是由于其通过减少PD的保护作用及其在赋予EZH2介导的PD表观遗传调控中的伪装作用。EZH2-FOXP3相互作用对于神经保护性Treg细胞活性是必需的。因此,我们合成了FTY720纳米颗粒，以改善FTY720在体内PD模型中的保护功效，以探索PP2A介导的信号传导。我们证实了FTY720NP的形成，行为和蛋白质表达研究的结果表明，我们的纳米制剂具有显著的神经保护作用。在神经保护机制的探索中，几行证据证实FTY720NP介导的PP2A/EZH2/FOXP3信号传导在体内PD治疗中诱导Treg细胞的作用。总之,我们的纳米制剂在临床设置中通过诱导PP2A诱导的表观遗传调节介导的神经免疫调节来缓解PD具有新的潜力。
