Ubiquilin-2 liquid droplets catalyze α-synuclein fibril formation
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Liquid‒liquid phase separation (LLPS) and the subsequent liquid‒solid transition are thought to be common aggregation mechanisms of neurodegeneration-associated proteins. α-Synuclein (α-syn), whose aggregation represents the major pathological hallmark of Parkinson’s disease, is reported to undergo LLPS, which accelerates oligomer and aggregate formation in vitro and in vivo ; however, the precise molecular events involved in the early stages of α-syn aggregation remain controversial. In the present study, α-syn aggregation was promoted by liquid droplets formed by ubiquilin-2 (UBQLN2) rather than directly by the LLPS of α-syn. During the liquid–gel/solid transition of UBQLN2 droplets, α-syn within the droplets was transformed into pathogenic fibrils both in vitro and within cells. The small compound SO286 inhibited both UBQLN2 self-interaction and α-syn–UBQLN2 interaction by binding to the STI1 region of UBQLN2, thereby impairing α-syn aggregation. These results indicate that UBQLN2 droplets catalyze α-syn fibril formation and suggest that small molecules that target fibrillation-catalyzing proteins may represent a promising strategy for the development of therapeutics against neurodegenerative diseases.
Significance statement
Although the fibril formation of α-synuclein is a major driver of Parkinson’s disease pathology, the mechanisms of its early stages remain unclear. Here, we demonstrated in vitro and in cells that ubiquilin-2 (UBQLN2) droplets, formed via liquid‒liquid phase separation, absorbed soluble α-synuclein and promoted the fibril formation of α-synuclein through their liquid–gel/solid transition. This result suggests a previously unrecognized role for UBQLN2 in catalyzing α-synuclein fibril formation via its own liquid‒liquid phase separation. Furthermore, a small molecule targeting the STI1 region of UBQLN2 inhibited both the liquid‒solid transition of UBQLN2 and the interaction between UBQLN2 and α-synuclein, thereby suppressing α-synuclein aggregation. These findings suggest a new approach for the development of therapeutic interventions for Parkinson’s disease.
