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

• Published in: The Journal of biological chemistry 2024-03, Vol.300 (3), p.105667-105667, Article 105667
• Main Authors: Liu, He-Ning, Wang, Ting, Hu, Jin-Jian, Chen, Long, Shi, Xiangyan, Li, Yan-Mei, Luo, Shi-Zhong
• Format: Article
• Language: English
• Subjects: aggregation; cophase separation; oligomer toxicity; SERF; α-Synuclein
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2024.105667

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.