The universally abundant polyphosphate (polyP) accelerates fibril formation of disease-related amyloids and protects against amyloid cytotoxicity. To gain insights into the mechanism(s) by which polyP exerts these effects, we focused on α-synuclein, a well-studied amyloid protein, which constitutes the major component of Lewy bodies found in Parkinson's disease. Here, we demonstrate that polyP is unable to accelerate the rate-limiting step of α-synuclein fibril formation but effectively nucleates fibril assembly once α-synuclein oligomers are formed. Binding of polyP to α-synuclein either during fibril formation or upon fibril maturation substantially alters fibril morphology and effectively reduces the ability of α-synuclein fibrils to interact with cell membranes. The effect of polyP appears to be α-synuclein fibril specific and successfully prevents the uptake of fibrils into neuronal cells. These results suggest that altering the polyP levels in the extracellular space might be a potential therapeutic strategy to prevent the spreading of the disease.

中文翻译：

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深入了解多磷酸盐对淀粉样蛋白细胞毒性的保护作用。

普遍存在的多磷酸盐（polyP）促进与疾病相关的淀粉样蛋白的原纤维形成，并防止淀粉样蛋白的细胞毒性。为了深入了解polyP发挥这些作用的机制，我们集中研究了α-突触核蛋白（一种经过充分研究的淀粉样蛋白），它构成了帕金森氏病中路易小体的主要成分。在这里，我们证明polyP无法加速α-突触核蛋白原纤维形成的限速步骤，但是一旦形成α-突触核蛋白低聚物，就可以有效地成核原纤维组装体。在原纤维形成期间或原纤维成熟时，polyP与α-突触核蛋白的结合实质上改变了原纤维形态，并有效地降低了α-突触核蛋白原纤维与细胞膜相互作用的能力。polyP的作用似乎是α-突触核蛋白原纤维特异性的，并成功地阻止了原纤维被吸收到神经元细胞中。这些结果表明，改变细胞外空间中的polyP水平可能是预防疾病传播的潜在治疗策略。