Chemical Biology Unit, Institute of Nano Science and Technology, Sector-81, Knowledge City, Sahibzada Ajit Singh Nagar, Mohali 140306, Punjab, India.
Department of Chemical Sciences, Indian Institute of Science Education and Research, Sector-81, Knowledge City, Sahibzada Ajit Singh Nagar, Mohali 140306, Punjab, India.
ACS Chem Neurosci. 2024 Nov 6;15(21):4055-4065. doi: 10.1021/acschemneuro.4c00459. Epub 2024 Oct 15.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the aggregation of α-synuclein into toxic amyloid fibrils. Recent research suggests that bile acids altered in PD may influence their aggregation. This study investigates the effects of lithocholic acid (LCA) and deoxycholic acid (DCA) on α-synuclein aggregation and toxicity. LCA significantly accelerates aggregation, reducing the lag phase by 75%, while DCA has a milder impact, decreasing the lag phase by 30%. Binding studies show that LCA interacts with the NAC region and DCA with the N-terminal region of α-synuclein. Aggregation assays and electrophoresis reveal that LCA promotes the formation of toxic, SDS-resistant oligomers more effectively than DCA. Cytotoxicity assays confirm a lower cell viability in LCA-treated samples. Additionally, combined LCA and DCA treatment results in enhanced aggregation and toxicity, indicating a synergistic effect. These findings highlight the role of bile acids in α-synuclein aggregation and PD pathogenesis, suggesting that targeting bile acid metabolism could be a therapeutic strategy for PD.
帕金森病（PD）是一种神经退行性疾病，其特征是α-突触核蛋白聚集形成毒性淀粉样纤维。最近的研究表明，PD 中改变的胆汁酸可能会影响其聚集。本研究调查了石胆酸（LCA）和脱氧胆酸（DCA）对α-突触核蛋白聚集和毒性的影响。LCA 显著加速了聚集，将潜伏期缩短了 75%，而 DCA 的影响较小，将潜伏期缩短了 30%。结合研究表明，LCA 与 NAC 区域相互作用，而 DCA 与α-突触核蛋白的 N 端区域相互作用。聚集分析和电泳表明，LCA 比 DCA 更有效地促进了有毒的、不溶于 SDS 的寡聚物的形成。细胞毒性试验证实了 LCA 处理的样品中细胞活力较低。此外，LCA 和 DCA 的联合处理导致聚集和毒性增强，表明存在协同作用。这些发现强调了胆汁酸在α-突触核蛋白聚集和 PD 发病机制中的作用，表明靶向胆汁酸代谢可能是 PD 的一种治疗策略。
