The amyloid aggregation of α-synuclein (α-Syn) is highly associated with Parkinson’s disease (PD). Discovering α-Syn amyloid inhibitors is one of the strategies for PD therapies. Recent studies suggested that α-Syn undergoes phase separation to accelerate amyloid aggregation. Molecules modulating α-Syn phase separation or transition have the potential to regulate amyloid aggregation. Here, we discovered that curcumin, a small natural molecule, interacts with α-Syn during phase separation. Our study showed that curcumin neither affects the formation of α-Syn condensates nor influences the initial morphology of α-Syn condensates. However, curcumin decreases the fluidity of α-Syn inside the condensates and efficiently inhibits α-Syn from turning into an amyloid. It also inhibits the amyloid aggregations of PD disease-related α-Syn E46K and H50Q mutants under phase separation. Furthermore, curcumin can destabilize preformed α-Syn amyloid aggregates in the condensates. Together, our findings demonstrate that curcumin regulates α-Syn amyloid formation during protein phase separation and reveal that α-Syn amyloid aggregation under phase separation can be modulated by small molecules.

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

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The Lewy bodies and Lewy neurites are key pathological hallmarks of Parkinson’s disease (PD). Single-point mutations associated with familial PD cause α-synuclein (α-Syn) aggregation, leading to the formation of Lewy bodies and Lewy neurites. Recent studies suggest α-Syn nucleates through liquid–liquid phase separation (LLPS) to form amyloid aggregates in a condensate pathway. How PD-associated mutations affect α-Syn LLPS and its correlation with amyloid aggregation remains incompletely understood. Here, we examined the effects of five mutations identified in PD, A30P, E46K, H50Q, A53T, and A53E, on the phase separation of α-Syn. All other α-Syn mutants behave LLPS similarly to wild-type (WT) α-Syn, except that the E46K mutation substantially promotes the formation of α-Syn condensates. The mutant α-Syn droplets fuse to WT α-Syn droplets and recruit α-Syn monomers into their droplets. Our studies showed that α-Syn A30P, E46K, H50Q, and A53T mutations accelerated the formation of amyloid aggregates in the condensates. In contrast, the α-Syn A53E mutant retarded the aggregation during the liquid-to-solid phase transition. Finally, we observed that WT and mutant α-Syn formed condensates in the cells, whereas the E46K mutation apparently promoted the formation of condensates. These findings reveal that familial PD-associated mutations have divergent effects on α-Syn LLPS and amyloid aggregation in the phase-separated condensates, providing new insights into the pathogenesis of PD-associated α-Syn mutations.