Xu Bingkuan, Chen Jing, Liu Yinghui
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China.
ACS Omega. 2022 Aug 15;7(34):30281-30290. doi: 10.1021/acsomega.2c03534. eCollection 2022 Aug 30.
The amyloid aggregation of α-synuclein (α-Syn) is highly associated with Parkinson's disease (PD). Discovering α-Syn amyloid inhibitors is one of the strategies for PD therapies. Recent studies suggested that α-Syn undergoes phase separation to accelerate amyloid aggregation. Molecules modulating α-Syn phase separation or transition have the potential to regulate amyloid aggregation. Here, we discovered that curcumin, a small natural molecule, interacts with α-Syn during phase separation. Our study showed that curcumin neither affects the formation of α-Syn condensates nor influences the initial morphology of α-Syn condensates. However, curcumin decreases the fluidity of α-Syn inside the condensates and efficiently inhibits α-Syn from turning into an amyloid. It also inhibits the amyloid aggregations of PD disease-related α-Syn E46K and H50Q mutants under phase separation. Furthermore, curcumin can destabilize preformed α-Syn amyloid aggregates in the condensates. Together, our findings demonstrate that curcumin regulates α-Syn amyloid formation during protein phase separation and reveal that α-Syn amyloid aggregation under phase separation can be modulated by small molecules.
α-突触核蛋白（α-Syn）的淀粉样聚集与帕金森病（PD）高度相关。发现α-Syn淀粉样蛋白抑制剂是PD治疗策略之一。最近的研究表明，α-Syn经历相分离以加速淀粉样聚集。调节α-Syn相分离或转变的分子有可能调节淀粉样聚集。在此，我们发现姜黄素这种小分子天然物质在相分离过程中与α-Syn相互作用。我们的研究表明，姜黄素既不影响α-Syn凝聚物的形成，也不影响α-Syn凝聚物的初始形态。然而，姜黄素会降低凝聚物内部α-Syn的流动性，并有效抑制α-Syn转变为淀粉样蛋白。它还能在相分离条件下抑制与PD疾病相关的α-Syn E46K和H50Q突变体的淀粉样聚集。此外，姜黄素能使凝聚物中预先形成的α-Syn淀粉样聚集体不稳定。总之，我们的研究结果表明姜黄素在蛋白质相分离过程中调节α-Syn淀粉样蛋白的形成，并揭示相分离条件下的α-Syn淀粉样聚集可被小分子调节。
