The chemistry of molecules in solution is dynamic and complex, such as the spontaneous liquid-liquid phase separation in which a solution divides into regions of greater and lesser concentrations to form droplets. This process is important in the formation of protein aggregates involved in neurodegenerative disease. Here, researchers show that the α-synuclein that misfolds and aggregates to cause Parkinson's disease does not undergo liquid-liquid phase separation on its own, but rather is dragged into the liquid-liquid phase separation and droplet formation of another protein, UBQLN2. This suggests possible novel targets to interfere in this chemistry.
Some neurodegenerative disease-associated proteins form liquid droplets via liquid-liquid phase separation (LLPS). Over time, these droplets transition from a highly labile liquid state to a hydrogel state, and eventually to a solid-like condensate, via self-interaction and oligomerization of the proteins within, thereby leading to the formation of amyloid fibrils. Recently, α-synuclein (α-syn) has been reported to be one such protein. 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 molecule 1,2,3,6-tetra-O-benzoyl-muco-inositol (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.
Link: https://doi.org/10.1038/s44318-025-00591-1
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