School of Pharmacy, Henan University, Kaifeng, Henan 475004, China.
Chem Commun (Camb). 2024 Jun 25;60(52):6581-6590. doi: 10.1039/d4cc01591f.
The deposition of α-synuclein (α-Syn) in Lewy bodies serves as a prominent pathological hallmark of Parkinson's disease (PD). Recent research has revealed that α-Syn can undergo liquid-liquid phase separation (LLPS) during its fibrillization. Over time, the maturation of the resulting condensates leads to a liquid-to-solid phase transition (LSPT) ultimately resulting in the amyloid deposition in cells which is linked to the pathogenesis and development of PD. Herein, we summarize the understanding of α-Syn aggregation which can be described by nucleation and elongation steps to obtain insights into the correlation of protein aggregation, structural polymorphism, and PD progression. Additionally, we discuss the LLPS phenomena of α-Syn and heterotypic cross-amyloid interactions with a focus on aberrant LSPT in the aggregation process. Exploring the underlying mechanisms and interplay between α-Syn aberrant aggregation, pathological phase transitions, and PD pathogenesis will shed light on potential therapeutic interventions.
α-突触核蛋白（α-Syn）在路易体中的沉积是帕金森病（PD）的一个显著病理学标志。最近的研究表明，α-Syn 在其纤维化过程中可以发生液-液相分离（LLPS）。随着时间的推移，由此产生的凝聚物的成熟导致液-固相变（LSPT），最终导致细胞中的淀粉样沉积，这与 PD 的发病机制和发展有关。本文总结了对 α-Syn 聚集的理解，可以通过成核和延伸步骤来描述，以深入了解蛋白质聚集、结构多态性和 PD 进展之间的相关性。此外，我们还讨论了 α-Syn 的 LLPS 现象和异质交叉淀粉样相互作用，重点讨论了聚集过程中异常的 LSPT。探索 α-Syn 异常聚集、病理性相变和 PD 发病机制之间的潜在机制和相互作用将为潜在的治疗干预提供启示。
