Fig. 6: Rationally designed β-Syn derived peptides inhibit the LSPS of α-Syn and protect against α-Syn-induced neurodegeneration.

a A simulated low-energy binding conformation of α-Syn and β-Syn complex. The interaction surface is shown in the zoomed box. b Workflow for the screening and evaluation of peptides that inhibit α-Syn phase separation. c Representative confocal images of α-Syn (100 μM, 10% Rho-α-Syn) in the presence of β-Syn (100 μM) or peptides (500 μM). α-Syn labeled with Rhodamine B (Rho) exhibits red fluorescence. Scale bar, 5 μm. The experiments were carried out in the presence of 20% PEG. d Normalized FRAP recovery curves of α-Syn (100 μM) condensates in the presence of β-Syn (100 μM) or antagonistic peptides (500 μM), n = 6 condensates per group. The experiments were carried out in the presence of 20% PEG. e Representative confocal images of NL5901 head with or without peptides. α-Syn fused with YFP gives green fluorescence. Scale bar, 100 μm. f Normalized FRAP recovery curves of α-Syn inclusions in NL5901 after treated with or without peptides (100 μM), n = 6 inclusions per group. g Effects of antagonistic peptides (100 μM) on thrashing movement of NL5901. Experiments were repeated 3 times, 10 worms were used for each condition. ^**P_{Thrashing (NL5901 vs NL5901 + P0)} < 0.0001, ^**P_{Thrashing (NL5901 vs NL5901 + P1)} < 0.0001, ^**P_{Thrashing (NL5901 vs NL5901 + P3)} < 0.0001, ^**P_{Thrashing (NL5901 vs NL5901 + P4)} < 0.0001, ^**P_{Thrashing (NL5901 vs NL5901 + P5)} < 0.0001. h, i Effects of peptides (100 μM) on survival curves and median lifespan of NL5901. Experiments were repeated at least 3 times, 20 worms were used for each condition. ^**P_{median lifespan (NL5901 vs NL5901 + P0)} = 0.0004, ^**P_{median lifespan (NL5901 vs NL5901 + P1)} = 0.001, ^**P_{median lifespan (NL5901 vs NL5901 + P3)} = 0.0004, ^**P_{median lifespan (NL5901 vs NL5901 + P4)} < 0.0001, ^**P_{median lifespan (NL5901 vs NL5901 + P5)} < 0.0001. j A working model of β-Syn effect on α-Syn liquid-liquid phase separation (LLPS) and liquid-solid phase separation (LSPS). Wildtype β-Syn facilitates the LLPS of α-Syn and delays the LSPS of α-Syn, while β-Syn mutations lose this ability. And peptides derived from β-Syn can inhibit the aggregation of α-Syn. Data are presented as mean ± SD, one-way ANOVA was used for multiple experimental groups without adjustment. ^**P < 0.01; ns, no significance. c–i At least three independent experiments were performed with similar results. Source data are provided as a Source Data file.