PASTEUR, Department of Chemistry, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 75005 Paris, France.
Institut Francois Jacob (MIRCen), CEA, CNRS, Fontenay-aux-Roses, France.
Sci Adv. 2023 Aug 18;9(33):eadg5663. doi: 10.1126/sciadv.adg5663. Epub 2023 Aug 16.
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.
α-突触核蛋白（α-Syn）聚集成具有朊病毒样特征的纤维与路易体病理和各种突触核蛋白病密切相关。新兴研究表明，α-Syn 可以通过相分离形成液滴。这些液滴在聚集和疾病中的作用仍然难以捉摸，α-Syn 纤维和 α-Syn 液滴之间的相互作用仍未被探索，这可能是由于难以在细胞中触发 α-Syn 液滴的形成。为了解决这一差距，我们开发了一种在细胞中控制 α-Syn 液滴组装/拆卸的测定方法，并在暴露于预先形成的 α-Syn 纤维状多形体时对其进行了研究。纤维触发了液态 α-Syn 液滴向固态结构的演变，显示出不断生长的针状延伸，并表现出病理性淀粉样特征。未经历相分离的 α-Syn 没有引起这种变化。因此，我们提出了一个模型，其中液滴中的 α-Syn 为外源性纤维状种子的生长提供燃料，从而加速致病性聚集物的朊病毒样传播。
