Laboratory of Neuropharmacology, EBRI Rita Levi-Montalcini Foundation, Rome, Italy.
Laboratory of Neuropharmacology, EBRI Rita Levi-Montalcini Foundation, Rome, Italy; Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
Biochem Pharmacol. 2020 Aug;178:114066. doi: 10.1016/j.bcp.2020.114066. Epub 2020 Jun 2.
Oxidative stress is a toxic cellular condition, strictly related to inflammation and known to be a common feature of many neurodegenerative diseases. The imbalanced redox state modifies several molecular processes including protein SUMOylation, JNK and Tau protein activation, important actors in Alzheimer's disease. In this study, we showed a strong interaction among SUMO-1-JNK-Tau proteins and their molecular targets in an in vitro model (SHSY5Y cell line) of oxidative stress in which a significant reduction of cell viability and an augmented cell death was induced by increased doses of H2O2. The evoked oxidative stress led to a deficiency in the degradation system showing altered levels of Caspase-3, LC3BII/I and Ubiquitin. Curcumin, a natural compound with anti-oxidant and anti-inflammatory effects, demonstrated to tackle oxidative stress re-equilibrating SUMO-1, JNK and Tau functions. Importantly, 5 μM of curcumin induced an efficient recovery of cell viability, a reduction of cell death and a normalization of altered protein degradation marker levels. Interestingly, we found that H2O2 treatment induced a strong co-localization of SUMO-1-p-JNK-Tau proteins in nuclear bodies (NBs) and that curcumin was able to reduce these nuclear aggregates. These results highlight the SUMO-1-JNK-Tau axis key role in oxidative stress and the protective effect of curcumin against this pathological event, focusing on the importance of SUMO/deSUMOylation balance to regulate essential cellular processes.
氧化应激是一种有毒的细胞状态，与炎症密切相关，被认为是许多神经退行性疾病的共同特征。失衡的氧化还原状态会改变包括蛋白质 SUMOylation、JNK 和 Tau 蛋白激活在内的几种分子过程，这些都是阿尔茨海默病的重要因素。在这项研究中，我们在体外氧化应激模型（SHSY5Y 细胞系）中显示了 SUMO-1-JNK-Tau 蛋白及其分子靶标之间的强烈相互作用，其中增加 H2O2 的剂量会导致细胞活力显著降低和细胞死亡增加。诱发的氧化应激导致降解系统出现缺陷，表现为 Caspase-3、LC3BII/I 和泛素的水平发生改变。姜黄素是一种具有抗氧化和抗炎作用的天然化合物，被证明可以通过重新平衡 SUMO-1、JNK 和 Tau 的功能来应对氧化应激。重要的是，5 μM 的姜黄素诱导了细胞活力的有效恢复，细胞死亡的减少和改变的蛋白降解标记物水平的正常化。有趣的是，我们发现 H2O2 处理诱导了 SUMO-1-p-JNK-Tau 蛋白在核体（NBs）中的强烈共定位，而姜黄素能够减少这些核聚集。这些结果突出了 SUMO-1-JNK-Tau 轴在氧化应激中的关键作用，以及姜黄素对这种病理事件的保护作用，强调了 SUMO/deSUMOylation 平衡对调节基本细胞过程的重要性。
