Visser, B.; van Haren, M.; Lipinski, W.; van Leijenhorst-Groener, K.; Claessens, M.; Queiros, M.; Ramos, C.; Spruijt, E.

The aggregation of amyloidogenic proteins is linked to age-related diseases. The presence of interfaces can affect their aggregation mechanism, often speeding up aggregation. -Synuclein (Syn) can adsorb to biomolecular condensates, leading to heterogenous nucleation and faster aggregation. Understanding the mechanism underlying localization of amyloidogenic proteins at condensate interfaces is crucial for developing strategies to prevent or reverse their binding. We show that Syn localization to the surface of peptide-based heterotypic condensates is an adsorption process governed by the protein\'s condensate-amphiphilic nature. Adsorption occurs in multiple layers and levels off at micromolar concentrations. Based on these findings, we design three strategies to modulate Syn accumulation: (i) addition of biomolecules that decrease the condensate {zeta}-potential, such as NTPs and RNA, (ii) competitive adsorption of proteins targeting the condensate interface, such as G3BP1, DDX4-YFP, EGFP-NPM1, Hsp70, Hsc70, and (iii) preferential adsorption of Syn to membranes. Removing Syn from the condensate interface slows aggregation, highlighting potential cellular control over protein adsorption and implications for therapeutic strategies.