The disordered protein SERF promotes α-Synuclein aggregation through liquid-liquid phase separation

The aggregation of α-Synuclein (α-Syn) into amyloid fibrils is the hallmark of Parkinson's disease (PD). Under stress or other pathological conditions, the accumulation of α-Syn oligomers is the main contributor to the cytotoxicity. A potential approach for treating PD 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 co-phase 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 SERF plays a role in the interactions that occur during co-phase separation. Within these droplets, α-Syn undergoes a gradual transformation from solid condensates to amyloid fibrils, while SERF is excluded from the condensates and dissolves into the solution. Notably, in vivo experiments show that SERF co-phase separation with α-Syn significantly reduces the deposition of α-Syn oligomers and decreases its cellular toxicity under stress. These findings suggest that SERF accelerates the conversion of α-Syn from highly toxic oligomers to less toxic fibrils through co-phase separation, thereby mitigating the biological damage of α-Syn aggregation.