Due to the increase in life expectancy worldwide, age-related disorders such as neurodegenerative diseases (NDs) have become more prevalent. Conventional treatments comprise drugs that only attenuate some of the symptoms, but fail to arrest or delay neuronal proteotoxicity that characterizes these diseases. Due to their diverse biological activities, imidazole rings are intensively explored as powerful scaffolds for the development of new bioactive molecules. By using C. elegans, our work aims to explore novel biological roles for these compounds. To this end, we have tested the in vivo anti-proteotoxic effects of imidazolium salts. Since NDs have been largely linked to impaired antioxidant defense mechanisms, we focused on 1-Mesityl-3-(3-sulfonatopropyl) imidazolium (MSI), one of the imidazolium salts that we identified as capable of improving iron-induced oxidative stress resistance in wild-type animals. By combining mutant and gene expression analysis we have determined that this protective effect depends on the activation of the Heat Shock Transcription Factor (HSF-1), whereas it is independent of other canonical cytoprotective molecules such as abnormal Dauer Formation-16 (DAF-16/FOXO) and Skinhead-1 (SKN-1/Nrf2). To delve deeper into the biological roles of MSI, we analyzed the impact of this compound on previously established C. elegans models of protein aggregation. We found that MSI ameliorates β-amyloid-induced paralysis in worms expressing the pathological protein involved in Alzheimer’s Disease. Moreover, this compound also delays age-related locomotion decline in other proteotoxic C. elegans models, suggesting a broad protective effect. Taken together, our results point to MSI as a promising anti-proteotoxic compound and provide proof of concept of the potential of imidazole derivatives in the development of novel therapies to retard age-related proteotoxic diseases.

由于全球预期寿命的增加，与年龄相关的疾病如神经退行性疾病 (NDs) 变得更加普遍。常规治疗包括仅减轻某些症状但不能阻止或延迟表征这些疾病的神经元蛋白毒性的药物。由于其多样化的生物活性，咪唑环作为强大的支架被深入探索，用于开发新的生物活性分子。通过使用秀丽隐杆线虫，我们的工作旨在探索这些化合物的新生物学作用。为此，我们测试了体内咪唑盐的抗蛋白毒性作用.由于 ND 在很大程度上与抗氧化防御机制受损有关，因此我们专注于 1-Mesityl-3-(3-sulfonatopropyl) 咪唑鎓 (MSI)，这是一种咪唑鎓盐，我们确定它能够改善铁诱导的氧化应激抗性野生型动物。通过结合突变体和基因表达分析，我们确定这种保护作用取决于热休克转录因子 (HSF-1) 的激活，而它独立于其他典型的细胞保护分子，例如异常 Dauer Formation-16 (DAF-16 /FOXO) 和光头 1 (SKN-1/Nrf2)。为了深入研究 MSI 的生物学作用，我们分析了这种化合物对先前建立的影响秀丽隐杆线虫蛋白质聚集模型。我们发现 MSI 可改善表达与阿尔茨海默病相关的病理蛋白的蠕虫中 β-淀粉样蛋白诱导的麻痹。此外，这种化合物还可以延缓其他蛋白质毒性中与年龄相关的运动下降秀丽隐杆线虫模型，表明具有广泛的保护作用。总之，我们的结果表明 MSI 是一种有前途的抗蛋白毒性化合物，并为咪唑衍生物在开发新疗法以延缓与年龄相关的蛋白毒性疾病方面的潜力提供了概念证明。