α-Synuclein liquid condensates fuel fibrillar α-synuclein growth.

Leonard Piroska, Alexis Fenyi, Scott Thomas, Marie-Aude Plamont, Virginie Redeker, Ronald Melki, Zoher Gueroui

Science advances 2023 Aug 18

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

Citation

Leonard Piroska, Alexis Fenyi, Scott Thomas, Marie-Aude Plamont, Virginie Redeker, Ronald Melki, Zoher Gueroui. α-Synuclein liquid condensates fuel fibrillar α-synuclein growth. Science advances. 2023 Aug 18;9(33):eadg5663