The deposition of highly ordered fibrillar-type aggregates into inclusion bodies is a hallmark of neurodegenerative diseases such as Parkinson’s disease. The high stability of such amyloid fibril aggregates makes them challenging substrates for the cellular protein quality-control machinery 1 , 2 . However, the human HSP70 chaperone and its co-chaperones DNAJB1 and HSP110 can dissolve preformed fibrils of the Parkinson’s disease-linked presynaptic protein α-synuclein in vitro 3 , 4 . The underlying mechanisms of this unique activity remain poorly understood. Here we use biochemical tools and nuclear magnetic resonance spectroscopy to determine the crucial steps of the disaggregation process of amyloid fibrils. We find that DNAJB1 specifically recognizes the oligomeric form of α-synuclein via multivalent interactions, and selectively targets HSP70 to fibrils. HSP70 and DNAJB1 interact with the fibril through exposed, flexible amino and carboxy termini of α-synuclein rather than the amyloid core itself. The synergistic action of DNAJB1 and HSP110 strongly accelerates disaggregation by facilitating the loading of several HSP70 molecules in a densely packed arrangement at the fibril surface, which is ideal for the generation of ‘entropic pulling’ forces. The cooperation of DNAJB1 and HSP110 in amyloid disaggregation goes beyond the classical substrate targeting and recycling functions that are attributed to these HSP70 co-chaperones and constitutes an active and essential contribution to the remodelling of the amyloid substrate. These mechanistic insights into the essential prerequisites for amyloid disaggregation may provide a basis for new therapeutic interventions in neurodegeneration. The molecular steps that lead to the disaggregation of amyloid fibrils are shown to involve the synergistic action of HSP70 and its co-chaperones DNAJB1 and HSP110.

中文翻译：

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人 HSP70 对淀粉样蛋白分解的分子解剖

高度有序的纤维状聚集体沉积到包涵体中是帕金森病等神经退行性疾病的标志。这种淀粉样原纤维聚集体的高稳定性使它们成为细胞蛋白质质量控​​制机制 1, 2 的具有挑战性的底物。然而，人类 HSP70 分子伴侣及其共分子伴侣 DNAJB1 和 HSP110 可以在体外溶解帕金森病相关突触前蛋白 α-突触核蛋白的预形成原纤维 3, 4。这种独特活动的潜在机制仍然知之甚少。在这里，我们使用生化工具和核磁共振波谱来确定淀粉样原纤维分解过程的关键步骤。我们发现 DNAJB1 通过多价相互作用特异性识别 α-突触核蛋白的寡聚形式，并选择性地将 HSP70 靶向原纤维。HSP70 和 DNAJB1 通过暴露的、灵活的 α-突触核蛋白氨基和羧基末端而不是淀粉样蛋白核心本身与原纤维相互作用。DNAJB1 和 HSP110 的协同作用通过促进在原纤维表面密集排列的几个 HSP70 分子的加载，强烈加速解聚，这是产生“熵拉”力的理想选择。DNAJB1 和 HSP110 在淀粉样蛋白分解中的合作超出了传统的底物靶向和回收功能，这些功能归因于这些 HSP70 共伴侣，并且对淀粉样蛋白底物的重塑构成了积极和重要的贡献。这些对淀粉样蛋白解聚的基本先决条件的机械见解可能为神经退行性疾病的新治疗干预提供基础。导致淀粉样蛋白原纤维分解的分子步骤显示涉及 HSP70 及其共伴侣 DNAJB1 和 HSP110 的协同作用。