Ubiquilin-2 liquid droplets catalyze α-synuclein fibril formation.

Liquid-liquid phase separation (LLPS) and subsequent liquid-gel/solid transition are considered common aggregation mechanisms of proteins linked to neurodegenerative diseases. α-synuclein (α-syn), the main factor in Parkinson's disease pathology, has been reported to undergo LLPS, thereby accelerating aggregate formation. However, the precise molecular events involved in the early stages of α-syn aggregation remain controversial. In this study, we show that α-syn aggregation is promoted by droplets formed by ubiquilin-2 (UBQLN2), rather than by α-syn LLPS itself. During the liquid-gel/solid transition of UBQLN2 droplets, α-syn within the droplets transforms into pathogenic fibrils both in vitro and in cells. Immunohistochemistry of brain sections from sporadic Parkinson's disease patients revealed UBQLN2 in substantia nigra Lewy bodies, implicating UBQLN2 in α-syn aggregation in vivo. Furthermore, the small compound SO286 inhibited both UBQLN2 self-association and its interaction with α-syn by binding to the STI1 domain, thereby suppressing α-syn aggregation. These findings demonstrate that UBQLN2 droplets catalyze α-syn fibrillization and suggest that small molecules targeting fibril-catalyzing proteins such as UBQLN2 may represent a promising therapeutic approach for neurodegenerative diseases.