β-synuclein blocks α-synuclein condensate fusion to disrupt the maturation of phase separation.

The abnormal accumulation of α-synuclein (α-Syn) is a key feature of Parkinson's disease (PD) and other synucleinopathies. α-Syn undergoes liquid-liquid phase separation (LLPS) to accelerate the amyloid aggregation. β-synuclein (β-Syn) colocalizes with α-Syn and affects its aggregation. It remains poorly understood how the LLPS of α-Syn is regulated by β-Syn. Here, we find that β-Syn co-condenses with α-Syn, negatively regulating the LLPS of α-Syn. The mobility of α-Syn is reduced in α-Syn/β-Syn coacervates, diminishing the condensate fusion. β-Syn blocks the condensate growth and maturation of α-Syn phase separation but cannot reverse the condensation pathway. We show that dementia with Lewy bodies (DLB)-associated β-Syn mutations impair β-Syn's inhibitory role in α-Syn condensate fusion. β-Syn, but not its disease-associated mutants, can ameliorate α-Syn-caused dopaminergic neuron degeneration in Caenorhabditis elegans. These findings provide insights into the neuroprotection of β-Syn and the targeting of α-Syn phase separation in disease treatment.