In living cells, liquid condensates form in the cytoplasm and nucleoplasm via phase separation and regulate physiological processes. They also regulate aberrant aggregation of amyloid fibrils, a process linked to Alzheimer's and Parkinson's diseases. In the absence of condensates it has been shown that amyloid aggregation can be inhibited by molecular chaperones and rationally designed drugs. However it remains unknown how this drug- or chaperone-mediated inhibition of amyloid fibril aggregation is affected by phase-separated condensates. Here we study the interplay between protein aggregation, its inhibition and liquid-liquid phase separation. Our key finding is that the potency of inhibitors of amyloid formation can be strongly enhanced. We show that the corresponding mechanism relies on the colocalization of inhibitors and aggregates inside the liquid condensate. We provide experimentally testable physicochemical conditions under which the increase of inhibitor potency is most pronounced. Our work highlights the role of spatio-temporal heterogeneity in curtailing aberrant protein aggregation and suggests design principles for amyloid inhibitors accounting for partitioning of drugs into liquid condensates.

中文翻译：

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液体冷凝物增加淀粉样蛋白原纤维抑制剂的效力

在活细胞中，液体凝结物通过相分离在细胞质和核质中形成并调节生理过程。它们还调节淀粉样蛋白纤维的异常聚集，该过程与阿尔茨海默氏病和帕金森氏病有关。在没有缩合物的情况下，已经证明淀粉伴侣可以被分子伴侣和合理设计的药物抑制。然而，尚不清楚这种药物或伴侣介导的淀粉样蛋白原纤维聚集的抑制作用如何受到相分离的缩合物的影响。在这里，我们研究蛋白质聚集，其抑制和液-液相分离之间的相互作用。我们的关键发现是淀粉样蛋白形成抑制剂的功效可以大大增强。我们表明，相应的机制依赖于液体冷凝物中抑制剂和聚集体的共定位。我们提供了在实验上可测试的物理化学条件，在这些条件下，抑制剂效能的提高最为明显。我们的工作强调了时空异质性在减少异常蛋白质聚集中的作用，并提出了淀粉样蛋白抑制剂的设计原则，这些原则解释了将药物分配到液体冷凝物中的情况。