PDF(Pubmed)
Abstract：
The aggregation of α-Synuclein (α-Syn) into amyloid fibrils is the hallmark of Parkinson\'s disease. Under stress or other pathological conditions, the accumulation of α-Syn oligomers is the main contributor to the cytotoxicity. A potential approach for treating Parkinson\'s disease involves preventing the accumulation of these α-Syn oligomers. In this study, we present a novel mechanism involving a conserved group of disorderly proteins known as small EDRK-rich factor (SERF), which promotes the aggregation of α-Syn through a cophase separation process. Using diverse methods like confocal microscopy, fluorescence recovery after photobleaching assays, solution-state NMR spectroscopy, and Western blot, we determined that the N-terminal domain of SERF1a plays a role in the interactions that occur during cophase separation. Within these droplets, α-Syn undergoes a gradual transformation from solid condensates to amyloid fibrils, while SERF1a is excluded from the condensates and dissolves into the solution. Notably, in vivo experiments show that SERF1a cophase separation with α-Syn significantly reduces the deposition of α-Syn oligomers and decreases its cellular toxicity under stress. These findings suggest that SERF1a accelerates the conversion of α-Syn from highly toxic oligomers to less toxic fibrils through cophase separation, thereby mitigating the biological damage of α-Syn aggregation.
摘要：
α-突触核蛋白(α-Syn)聚集成淀粉样纤维是帕金森病(PD)的标志。在压力或其他病理条件下，α-Syn寡聚体的积累是细胞毒性的主要因素。治疗PD的潜在方法包括防止这些α-Syn低聚物的积累。在这项研究中,我们提出了一种新的机制，涉及一组保守的无序蛋白质，称为小EDRK丰富因子（SERF），通过共相分离过程促进α-Syn的聚集。使用不同的方法，如共聚焦显微镜，光漂白测定后的荧光恢复，溶液状态NMR光谱和蛋白质印迹，我们确定SERF的N端结构域在共相分离过程中发生的相互作用中起作用.在这些液滴中，α-Syn经历了从固体缩合物到淀粉样纤维的逐渐转变，而SERF从冷凝物中排除并溶解到溶液中。值得注意的是,体内实验表明，SERF与α-Syn的共相分离显着减少了α-Syn低聚物的沉积，并降低了其在应激下的细胞毒性。这些发现表明，SERF通过共相分离加速了α-Syn从高毒性低聚物到毒性较小的原纤维的转化，从而减轻α-Syn聚集的生物损伤。
