Several RNA binding proteins involved in membraneless organelles can form pathological amyloids associated with neurodegenerative diseases, but the mechanisms of how this aggregation is modulated remain elusive. Here we investigate how heterotypic protein–RNA interactions modulate the condensation and the liquid to amyloid transition of hnRNPA1A, a protein involved in amyothropic lateral sclerosis. In the absence of RNA, formation of condensates promotes hnRNPA1A aggregation and fibrils are localized at the interface of the condensates. Addition of RNA modulates the soluble to amyloid transition of hnRNPA1A according to different pathways depending on RNA/protein stoichiometry. At low RNA concentrations, RNA promotes both condensation and amyloid formation, and the catalytic effect of RNA adds to the role of the interface between the dense and dilute phases. At higher RNA concentrations, condensation is suppressed according to re-entrant phase behaviour but formation of hnRNPA1A amyloids is observed over longer incubation times. Our findings show how heterotypic nucleic acid–protein interactions affect the kinetics and molecular pathways of amyloid formation.

无膜细胞器中涉及的几种RNA结合蛋白可以形成与神经退行性疾病相关的病理性淀粉样蛋白，但如何调节这种聚集的机制仍然难以捉摸。在这里，我们研究异型蛋白-RNA 相互作用如何调节 hnRNPA1A（一种参与肌萎缩侧索硬化症的蛋白质）的凝结和液体到淀粉样蛋白的转变。在没有 RNA 的情况下，凝结物的形成促进 hnRNPA1A 聚集，并且原纤维位于凝结物的界面处。添加 RNA 可根据 RNA/蛋白质化学计量的不同途径调节 hnRNPA1A 从可溶性向淀粉样蛋白的转变。在低 RNA 浓度下，RNA 促进缩合和淀粉样蛋白形成，RNA 的催化作用增加了密相和稀相之间界面的作用。在较高的 RNA 浓度下，根据重入相行为，凝结受到抑制，但在较长的孵育时间内观察到 hnRNPA1A 淀粉样蛋白的形成。我们的研究结果表明异型核酸-蛋白质相互作用如何影响淀粉样蛋白形成的动力学和分子途径。