Differential effects of α-Synuclein monomers and seeds on the material properties of Tau condensates

ABSTRACT Tau and α-Synuclein (αSyn) frequently co-aggregate in various neurodegenerative disorders. Recently, Tau has been shown to form dynamic, liquid-like condensates that can recruit αSyn, and potentially serve as a precursor to pathological aggregation. However, the quantitative impact of αSyn on the material properties of these condensates remains elusive. Here, we measure the viscosity and interfacial tension of Tau condensates and determine how these properties are modulated by αSyn monomers and fibril seeds. We find that while both forms of αSyn partition efficiently into Tau condensates, they exert vastly different effects on the condensate’s material state. The viscosity of Tau condensates remains unchanged in the presence of αSyn monomers at concentrations up to 200 µM, accompanied by a moderate reduction in the condensates’ interfacial tension. In contrast, the addition of only 5 µM αSyn fibril seeds triggers rapid solidification of Tau condensates, manifested by a nearly 100-fold increase in condensate viscosity within one hour. These findings provide quantitative insights into condensate mechanics, highlighting the unique capacity of αSyn seeds to drive the liquid-to-solid transition of Tau condensates that may underlie the formation of pathological aggregates.