-Synuclein phase separation and amyloid aggregation are modulated by C-terminal truncations

The aggregation of alpha-synuclein (alpha-Syn) is a key pathological hallmark of Parkinson's disease (PD). alpha-Syn undergoes liquid-liquid phase separation (LLPS) to drive amyloid aggregation. How the LLPS of alpha-Syn is regulated remains largely unknown. Here, we discovered that the C-terminal region modulates alpha-Syn phase separation through electrostatic interactions. The wild-type (WT) and PD disease-related truncated alpha-Syn can co-exist in the condensates. The truncated alpha-Syn could dramatically promote WT alpha-Syn phase separation. Further studies demonstrated that the truncated alpha-Syn accelerated WT alpha-Syn turning to amyloid aggregates by modulation of phase separation. Together, our findings disclose the role of the C-terminal domain in the LLPS of alpha-Syn and pave the path for understanding the mechanism of truncated alpha-Syn in PD pathology.