| Autor: |
Piroska L; PASTEUR, Department of Chemistry, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 75005 Paris, France., Fenyi A; Institut Francois Jacob (MIRCen), CEA, CNRS, Fontenay-aux-Roses, France., Thomas S; PASTEUR, Department of Chemistry, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 75005 Paris, France., Plamont MA; PASTEUR, Department of Chemistry, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 75005 Paris, France., Redeker V; Institut Francois Jacob (MIRCen), CEA, CNRS, Fontenay-aux-Roses, France., Melki R; Institut Francois Jacob (MIRCen), CEA, CNRS, Fontenay-aux-Roses, France., Gueroui Z; PASTEUR, Department of Chemistry, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 75005 Paris, France. |
| Abstrakt: |
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. |
