BioISI-Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal.
Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal.
Int J Mol Sci. 2024 Feb 1;25(3):1787. doi: 10.3390/ijms25031787.
Proteinaceous aggregates accumulate in neurodegenerative diseases such as Alzheimer's Disease (AD), inducing cellular defense mechanisms and altering the redox status. S100 pro-inflammatory cytokines, particularly S100B, are activated during AD, but recent findings reveal an unconventional molecular chaperone role for S100B in hindering Aβ aggregation and toxicity. This suggests a potential protective role for S100B at the onset of Aβ proteotoxicity, occurring in a complex biochemical environment prone to oxidative damage. Herein, we report an investigation in which extracellular oxidative conditions are mimicked to test if the susceptibility of S100B to oxidation influences its protective activities. Resorting to mild oxidation of S100B, we observed methionine oxidation as inferred from mass spectrometry, but no cysteine-mediated crosslinking. Structural analysis showed that the folding, structure, and stability of oxidized S100B were not affected, and nor was its quaternary structure. However, studies on Aβ aggregation kinetics indicated that oxidized S100B was more effective in preventing aggregation, potentially linked to the oxidation of Met residues within the S100:Aβ binding cleft that favors interactions. Using a cell culture model to analyze the S100B functions in a highly oxidative milieu, as in AD, we observed that Aβ toxicity is rescued by the co-administration of oxidized S100B to a greater extent than by S100B. Additionally, results suggest a disrupted positive feedback loop involving S100B which is caused by its oxidation, leading to the downstream regulation of IL-17 and IFN-α2 expression as mediated by S100B.
蛋白质聚集物在神经退行性疾病如阿尔茨海默病（AD）中积累，诱导细胞防御机制并改变氧化还原状态。S100 促炎细胞因子，特别是 S100B，在 AD 期间被激活，但最近的发现揭示了 S100B 在阻止 Aβ聚集和毒性方面具有非常规的分子伴侣作用。这表明 S100B 在 Aβ蛋白毒性发生时具有潜在的保护作用，而 Aβ蛋白毒性发生在易受氧化损伤的复杂生化环境中。在此，我们报告了一项研究，其中模拟细胞外氧化条件以测试 S100B 对氧化的敏感性是否会影响其保护活性。通过对 S100B 进行轻度氧化，我们观察到了质谱推断的蛋氨酸氧化，但没有半胱氨酸介导的交联。结构分析表明，氧化 S100B 的折叠、结构和稳定性未受影响，其四聚体结构也未受影响。然而，对 Aβ聚集动力学的研究表明，氧化 S100B 更有效地阻止聚集，这可能与 S100:Aβ结合裂缝内 Met 残基的氧化有关，有利于相互作用。使用细胞培养模型在高度氧化的环境中分析 S100B 的功能，如在 AD 中，我们观察到与 S100B 相比，氧化 S100B 的共给药更能挽救 Aβ毒性。此外，结果表明涉及 S100B 的破坏的正反馈环，这是由其氧化引起的，导致 S100B 介导的下游调节 IL-17 和 IFN-α2 的表达。
