Department of Physics and Astronomy, Clemson University, Clemson, South Carolina 29634, United States.
Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina 29634, United States.
J Phys Chem B. 2023 Jul 20;127(28):6241-6250. doi: 10.1021/acs.jpcb.3c01426. Epub 2023 Jul 6.
Amyloid aggregation describes the aberrant self-assembly of peptides into ordered fibrils characterized by cross-β spine cores and is associated with many neurodegenerative diseases and Type 2 diabetes. Oligomers, populated during the early stage of aggregation, are found to be more cytotoxic than mature fibrils. Recently, many amyloidogenic peptides have been reported to undergo liquid-liquid phase separation (LLPS)─a biological process important for the compartmentalization of biomolecules in living cells─prior to fibril formation. Understanding the relationship between LLPS and amyloid aggregation, especially the formation of oligomers, is essential for uncovering disease mechanisms and mitigating amyloid toxicity. In this Perspective, available theories and models of amyloid aggregation and LLPS are first briefly reviewed. By drawing analogies to gas, liquid, and solid phases in thermodynamics, a phase diagram of protein monomer, droplet, and fibril states separated by coexistence lines can be inferred. Due to the high free energy barrier of fibrillization kinetically delaying the formation of fibril seeds out of the droplets, a "hidden" monomer-droplet coexistence line extends into the fibril phase. Amyloid aggregation can then be described as the equilibration process from the initial "out-of-equilibrium" state of a homogeneous solution of monomers to the final equilibrium state of stable amyloid fibrils coexisting with monomers and/or droplets via the formation of metastable or stable droplets as the intermediates. The relationship between droplets and oligomers is also discussed. We suggest that the droplet formation of LLPS should be considered in future studies of amyloid aggregation, which may help to better understand the aggregation process and develop therapeutic strategies to mitigate amyloid toxicity.
淀粉样蛋白聚集描述了肽的异常自组装成具有交叉-β 棘突核心的有序纤维，与许多神经退行性疾病和 2 型糖尿病有关。寡聚体在聚集的早期阶段形成，被发现比成熟纤维具有更高的细胞毒性。最近，许多淀粉样蛋白原肽被报道在形成纤维之前经历液-液相分离（LLPS）——这是生物分子在活细胞中分区化的重要生物学过程。了解 LLPS 与淀粉样蛋白聚集之间的关系，特别是寡聚体的形成，对于揭示疾病机制和减轻淀粉样蛋白毒性至关重要。在这篇观点文章中，首先简要回顾了淀粉样蛋白聚集和 LLPS 的现有理论和模型。通过类比热力学中的气体、液体和固体相，可以推断出蛋白质单体、液滴和纤维状态的相图，由共存线分隔。由于纤维形成的自由能势垒很高，动力学上延迟了纤维种子从液滴中的形成，因此“隐藏”的单体-液滴共存线延伸到纤维相中。淀粉样蛋白聚集可以描述为从单体均匀溶液的初始“非平衡”状态到通过形成亚稳态或稳定的液滴作为中间体与单体和/或液滴共存的稳定淀粉样纤维的最终平衡状态的平衡过程。还讨论了液滴和寡聚体之间的关系。我们建议在未来的淀粉样蛋白聚集研究中应考虑 LLPS 的液滴形成，这可能有助于更好地理解聚集过程并开发减轻淀粉样蛋白毒性的治疗策略。
