A Theoretical Model reveals RNA sequestration in Alpha Synuclein Aggregates

Abstract

Nucleic acids can act as potent modulators of protein aggregation, and RNA is able to either hinder or facilitate protein assembly depending on the molecular context. Here we used a computational approach to characterize the physico-chemical properties of regions involved in amyloid aggregation. In different experimental datasets we observed that, while the core is hydrophobic and highly ordered, external regions, more disordered, display a distinct tendency to interact with nucleic acids. To validate our predictions, we performed aggregation assays with -synuclein (aS140), a non-nucleic acid binding amyloidogenic protein, and a mutant truncated at the acidic C-terminus (aS103) that is predicted to sequester RNA. For both aS140 and aS103 we observed acceleration of the aggregation upon RNA addition with a significantly stronger effect for aS103. Due to the favorable electrostatics, we observed enhanced nucleic-acid sequestration ability for aS103 that entrapped a larger amount of RNA. Overall, our research suggests that RNA sequestration is a rather common phenomenon linked to protein aggregation and constitutes a gain-of-function mechanism to be further investigated. STATEMENT OF SIGNIFICANCEOur study indicates that aggregation confers RNA-binding ability to non-RNA-binding proteins such as alpha synuclein. The sequestration of RNA upon protein aggregation might alter RNA homeostasis and impact multiple biochemical cascades.