α-Synuclein liquid condensates fuel fibrillar α-synuclein growth

• Published in: Science advances Vol. 9; no. 33; p. eadg5663
• Main Authors: Piroska, Leonard, Fenyi, Alexis, Thomas, Scott, Plamont, Marie-Aude, Redeker, Virginie, Melki, Ronald, Gueroui, Zoher
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science (AAAS) 18.08.2023; American Association for the Advancement of Science
• Subjects: alpha-Synuclein; Amyloid - chemistry; Biochemistry; Biomedicine and Life Sciences; Cellular Neuroscience; Life Sciences; Prions; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adg5663

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.