Institute of Nano Science and Technology, Habitat Centre, Phase-10, Mohali, Punjab, 160062, India.
Institute of Nano Science and Technology, Habitat Centre, Phase-10, Mohali, Punjab, 160062, India.
Carbohydr Polym. 2021 Feb 15;254:117435. doi: 10.1016/j.carbpol.2020.117435. Epub 2020 Nov 22.
Parkinson's disease (PD) develops due to oxidative stress, mitochondrial aberrations, posttranslational modification, and α-Synuclein (α-Syn) aggregation. The α-synucleinopathy is attributed to phosphorylation and aggregation of α-Syn. A strategy to degrade or reduce phosphorylated protein paves the way to develop PD therapy. Hence, the neuroprotective efficiency of PP2A (Protein phosphatase 2) activator FTY720, loaded chitosan nanoformulation has been evaluated in vitro and ex vivo experimental PD models. Bio-compatible chitosan-based nanocarriers have been utilized to enhance the bio-availability and neuroprotective effect of FTY720. The neuroprotective effect of characterized nanoformulation was determined by the downregulation of PD hallmark phospho-serine 129 (pSer129) α-Syn, with anti-oxidative and anti-inflammatory potentials. The neuroprotective mechanism uncovered novel physical interaction of PP2A and polycomb group of protein Enhancer of zeste homolog 2 to mediate ubiquitination and degradation of agglomerated pSer129 α-Syn. Indeed, this study establishes the neuroprotective potential of chitosan based FTY720 nanoformulations by PP2A mediated epigenetic regulation for PD prevention.
帕金森病（PD）的发生是由于氧化应激、线粒体异常、翻译后修饰和α-突触核蛋白（α-Syn）聚集。α-突触核蛋白病归因于α-Syn 的磷酸化和聚集。降解或减少磷酸化蛋白的策略为开发 PD 治疗铺平了道路。因此，已在体外和体内实验性 PD 模型中评估了蛋白磷酸酶 2A（PP2A）激活剂 FTY720 负载壳聚糖纳米制剂的神经保护效率。生物相容性壳聚糖纳米载体已被用于提高 FTY720 的生物利用度和神经保护作用。通过下调 PD 标志性磷酸丝氨酸 129（pSer129）α-Syn，以及抗氧化和抗炎作用，确定了特征纳米制剂的神经保护作用。神经保护机制揭示了 PP2A 和 Polycomb 组蛋白 Enhancer of zeste 同源物 2 的新型物理相互作用，介导聚集的 pSer129 α-Syn 的泛素化和降解。事实上，这项研究通过 PP2A 介导的表观遗传调控，确立了壳聚糖基 FTY720 纳米制剂在预防 PD 方面的神经保护潜力。
