Nanobiophysics, Faculty of Science and Technology, MESA + Institute for Nanotechnology and Technical Medical Centre, University of Twente, Enschede 7500 AE, The Netherlands.
Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven 5600 MB, The Netherlands.
ACS Chem Neurosci. 2024 May 1;15(9):1926-1936. doi: 10.1021/acschemneuro.4c00100. Epub 2024 Apr 18.
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.
α-突触核蛋白（αS）的聚集在帕金森病（PD）的发病机制中起着关键作用。虽然 PD 的发病与年龄有关，但细胞质量控制系统似乎在人类的大部分生命周期中调节 αS 的聚集。有趣的是，已经证明蛋白 14-3-3τ 可在各种模型中延迟 αS 聚集和 PD 的发作。然而，这种延迟背后的分子机制仍不清楚。我们的研究证实了 14-3-3τ 对 αS 聚集的延迟作用，并揭示了一种浓度依赖性关系。利用微尺度热泳（MST）和单分子爆发分析，我们定量了早期 αS 多聚体，并得出结论，这些多聚体表现出将它们归类为纳米级凝聚物的特性，这些凝聚物以合作的方式形成，先于纤维形成的临界核。重要的是，在支架蛋白 14-3-3τ 的存在下，αS 多聚体形成机制发生了巨大变化。我们的数据建模表明，14-3-3τ 调节多聚化过程，导致形成混合多聚体或共凝聚物，包含 αS 和 14-3-3τ。这些混合多聚体以非合作的方式形成。它们更小、更多，并且明显不在淀粉样形成的途径上。重要的是，14-3-3τ 因此在 αS 多聚体形成的早期阶段发挥作用，确保 αS 不会聚集，而是保持可溶性和功能性。这为 PD 的药理学调节提供了长期以来寻求的新途径。
