14-3-3τ as a Modulator of Early α-Synuclein Multimerization and Amyloid Formation

The aggregation of alpha-synuclein (alpha S) 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 alpha S aggregation throughout most human life. Intriguingly, the protein 14-3-3 tau has been demonstrated to delay alpha S aggregation and the onset of PD in various models. However, the molecular mechanisms behind this delay remain elusive. Our study confirms the delay in alpha S aggregation by 14-3-3 tau, unveiling a concentration-dependent relation. Utilizing microscale thermophoresis (MST) and single-molecule burst analysis, we quantified the early alpha S 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 alpha S multimer formation mechanism changes dramatically in the presence of scaffold protein 14-3-3 tau. Our data modeling suggests that 14-3-3 tau modulates the multimerization process, leading to the creation of mixed multimers or co-condensates, comprising both alpha S and 14-3-3 tau. These mixed multimers form in a noncooperative process. They are smaller, more numerous, and distinctively not on the pathway to amyloid formation. Importantly, 14-3-3 tau thus acts in the very early stage of alpha S multimerization, ensuring that alpha S does not aggregate but remains soluble and functional. This offers long-sought novel entries for the pharmacological modulation of PD.