AbstractNucleic acids can act as potent modulators of protein aggregation, and RNA has the ability to either hinder or facilitate protein assembly, depending on the molecular context. In this study, we utilized a computational approach to characterize the physico-chemical properties of regions involved in amyloid aggregation. In various experimental datasets, we observed that while the core is hydrophobic and highly ordered, external regions, which are more disordered, display a distinct tendency to interact with nucleic acids. To validate our predictions, we performed aggregation assays with alpha-synuclein (aS140), a non-nucleic acid-binding amyloidogenic protein, and a mutant truncated at the acidic C-terminus (aS103), which is predicted to have a higher tendency to interact with RNA. For both aS140 and aS103, we observed an acceleration of aggregation upon RNA addition, with a significantly stronger effect for aS103. Due to favorable electrostatics, we noted an enhanced nucleic acid sequestration ability for the aggregated aS103, allowing it to entrap a larger amount of RNA compared to the aggregated wild-type counterpart. Overall, our research suggests that RNA sequestration might be a common phenomenon linked to protein aggregation, constituting a gain-of-function mechanism that warrants further investigation.
