Inhibition of polyglutamine-mediated proteotoxicity by Astragalus membranaceus polysaccharide through the DAF-16/FOXO transcription factor in Caenorhabditis elegans

Late-onset neurodegenerative diseases are characterized by progressive accumulation of aggregation-prone proteins and global disruption of the proteostasis network, e.g. abnormal polyQ (polyglutamine) aggregation in Huntington's disease. Astragalus membranaceus polysaccharide (astragalan) has recently been shown to modulate aging and proteotoxic stress pathways. Using Caenorhabditis elegans models, we now show that astragalan not only reduces polyQ aggregation, but also alleviates the associated neurotoxicity. We also reveal that astragalan can extend the adult lifespan of wild-type and polyQ nematodes, indicating a connection of its anti-aging benefit with the toxicity-suppressing effect. Further examination demonstrates that astragalan can extend the lifespan of daf-2 and age-1, but not daf-16, mutant nematodes of the insulin-like aging and stress pathway, suggesting a lifespan-regulation signalling independent of DAF (abnormal dauer formation)-2/IGF-IR (insulin-like growth factor 1 receptor), but dependent on the DAF-16/FOXO (forkhead box 0) transcription factor, a pivotal integrator of divergent signalling pathways related to both lifespan regulation and stress resistance. We also show that a subset of DAF-16 downstream genes are regulated by astragalan, including the DAF-16 transcriptional target gene scl-20. which is itself constitutively up-regulated in transgenic polyQ nematodes. These findings, together with our previous work on LEA (late embryogenesis abundant) proteins and trehalose, provide a revealing insight into the potential of stress and lifespan regulators in the prevention of proteotoxic disorders.

迟发性神经退行性疾病的特征是易于聚集的蛋白质逐渐积累以及蛋白质稳态网络的全面紊乱，例如亨廷顿病中异常的多聚谷氨酰胺（polyQ）聚集。黄芪多糖（黄芪聚糖）最近被证明可调节衰老和蛋白毒性应激通路。通过秀丽隐杆线虫模型，我们现在发现黄芪聚糖不仅能减少多聚谷氨酰胺聚集，还能减轻相关的神经毒性。我们还揭示黄芪聚糖可延长野生型和多聚谷氨酰胺线虫的成年寿命，这表明其抗衰老益处与毒性抑制作用相关。进一步的检测表明，黄芪聚糖可延长胰岛素样衰老和应激通路中的daf - 2和age - 1突变线虫的寿命，但不能延长daf - 16突变线虫的寿命，这表明存在一种独立于DAF（异常 dauer形成）- 2/IGF - IR（胰岛素样生长因子1受体），但依赖于DAF - 16/FOXO（叉头框0）转录因子的寿命调节信号通路，DAF - 16/FOXO转录因子是与寿命调节和抗应激相关的不同信号通路的关键整合因子。我们还表明，黄芪聚糖可调节一部分DAF - 16下游基因，包括DAF - 16转录靶基因scl - 20，该基因在转基因多聚谷氨酰胺线虫中本身组成性上调。这些发现，连同我们之前关于晚期胚胎发生丰富（LEA）蛋白和海藻糖的研究，为应激和寿命调节剂在预防蛋白毒性疾病方面的潜力提供了深刻的见解。