a-Synuclein liquid condensates fuel fibrillar a-synuclein growth

a-Synuclein (a-Syn) aggregation into fibrils with prion-like features is intimately associated with Lewy pathology and various synucleinopathies. Emerging studies suggest that a-Syn could form liquid condensates through phase separation. The role of these condensates in aggregation and disease remains elusive and the interplay between a-Syn fibrils and a-Syn condensates remains unexplored, possibly due to difficulties in triggering the formation of a-Syn condensates in cells. To address this gap, we developed an assay allowing the controlled assembly/disassembly of a-Syn condensates in cells and studied them upon exposure to preformed a-Syn fibrillar polymorphs. Fibrils triggered the evolution of liquid a-Syn condensates into solid-like structures displaying growing needle-like extensions and exhibiting pathological amyloid hallmarks. No such changes were elicited on a-Syn that did not undergo phase separation. We, therefore, propose a model where a-Syn within condensates fuels exogenous fibrillar seeds growth, thus speeding up the prion-like propagation of pathogenic aggregates.

Automated summary

α-Synuclein aggregation is associated with various synucleinopathies. Recent studies suggest that α-Synuclein can form liquid condensates. This study investigates the interaction between condensates and fibrillar structures. The results show that fibrils can trigger the evolution of liquid condensates into solid-like structures with pathological features. α-Synuclein that did not undergo phase separation did not elicit such changes. The findings propose a model where α-Synuclein within condensates fuels the growth of exogenous fibrillar seeds, thereby accelerating the propagation of pathogenic aggregates.