The aggregation of α-synuclein (αS) plays a key role in Parkinson’s disease (PD) etiology. While the onset of PD is age-related, the cellular quality control system appears to regulate αS aggregation throughout most human life. Intriguingly, the protein 14-3-3τ has been demonstrated to delay αS aggregation and the onset of PD in various models. However, the molecular mechanisms behind this delay remain elusive. Our study confirms the delay in αS aggregation by 14-3-3τ, unveiling a concentration-dependent relation. Utilizing microscale thermophoresis (MST) and single-molecule burst analysis, we quantified the early αS multimers and concluded that these multimers exhibit properties that classify them as nanoscale condensates that form in a cooperative process, preceding the critical nucleus for fibril formation. Significantly, the αS multimer formation mechanism changes dramatically in the presence of scaffold protein 14-3-3τ. Our data modeling suggests that 14-3-3τ modulates the multimerization process, leading to the creation of mixed multimers or co-condensates, comprising both αS and 14-3-3τ. These mixed multimers form in a noncooperative process. They are smaller, more numerous, and distinctively not on the pathway to amyloid formation. Importantly, 14-3-3τ thus acts in the very early stage of αS multimerization, ensuring that αS does not aggregate but remains soluble and functional. This offers long-sought novel entries for the pharmacological modulation of PD.

中文翻译：

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14-3-3τ 作为早期 α-突触核蛋白多聚化和淀粉样蛋白形成的调节剂

α-突触核蛋白 (αS) 的聚集在帕金森病 (PD) 病因学中发挥着关键作用。虽然帕金森病的发病与年龄有关，但细胞质量控制系统似乎在大多数人的一生中调节 αS 聚集。有趣的是，在各种模型中，蛋白质 14-3-3τ 已被证明可以延迟 αS 聚集和 PD 的发生。然而，这种延迟背后的分子机制仍然难以捉摸。我们的研究证实了 14-3-3τ αS 聚集的延迟，揭示了浓度依赖性关系。利用微尺度热泳动 (MST) 和单分子爆发分析，我们对早期的 αS 多聚体进行了量化，并得出结论，这些多聚体表现出的特性将它们归类为在协作过程中形成的纳米级凝聚物，位于原纤维形成的关键核之前。值得注意的是，当支架蛋白 14-3-3τ 存在时，αS 多聚体形成机制会发生巨大变化。我们的数据模型表明，14-3-3τ 调节多聚化过程，导致产生混合多聚体或共缩合物，其中包含 αS 和 14-3-3τ。这些混合多聚体在非合作过程中形成。它们更小、数量更多，并且明显不参与淀粉样蛋白形成的途径。重要的是，14-3-3τ 因此在 αS 多聚化的早期阶段发挥作用，确保 αS 不会聚集，但保持可溶性和功能性。这为 PD 的药理调节提供了长期寻求的新思路。