Veiveris Dominykas, Kopustas Aurimas, Sulskis Darius, Mikalauskaite Kamile, Alsamsam Mohammad Nour, Tutkus Marijonas, Smirnovas Vytautas, Ziaunys Mantas
Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius LT-10257, Lithuania.
Department of Molecular Compound Physics, Center for Physical Sciences and Technology, Vilnius LT-10257, Lithuania.
Biomacromolecules. 2025 Jun 9;26(6):3525-3537. doi: 10.1021/acs.biomac.5c00130. Epub 2025 May 15.
Liquid-liquid phase separation of proteins and nucleic acids is a rapidly emerging field of study, aimed at understanding the process of biomolecular condensate formation. Recently, it has been discovered that different neurodegenerative disease-related proteins, such as α-synuclein and amyloid-β are capable of forming heterotypic droplets. Other reports have also shown non-LLPS cross-interactions between various amyloidogenic proteins and the resulting influence on their amyloid fibril formation. This includes the new discovery of pro-inflammatory S100A9 affecting the aggregation of both amyloid-β, as well as α-synuclein. In this study, we explore the formation of heterotypic droplets by S100A9 and α-synuclein. We show that their mixture is capable of assembling into both homotypic and heterotypic condensates and that this cross-interaction alters the aggregation mechanism of α-synuclein. These results provide insight into the influence of S100A9 on the process of neurodegenerative disease-related protein LLPS and aggregation.
蛋白质和核酸的液-液相分离是一个迅速兴起的研究领域，旨在了解生物分子凝聚物的形成过程。最近，人们发现不同的神经退行性疾病相关蛋白，如α-突触核蛋白和淀粉样β蛋白，能够形成异型液滴。其他报告也显示了各种淀粉样蛋白之间的非液-液相分离交叉相互作用以及对其淀粉样纤维形成的影响。这包括促炎蛋白S100A9影响淀粉样β蛋白和α-突触核蛋白聚集的新发现。在本研究中，我们探索了S100A9和α-突触核蛋白形成异型液滴的过程。我们表明，它们的混合物能够组装成同型和异型凝聚物，并且这种交叉相互作用改变了α-突触核蛋白的聚集机制。这些结果为S100A9对神经退行性疾病相关蛋白液-液相分离和聚集过程的影响提供了见解。
