Negatively charged α-Synuclein condensate modulates partitioning of molecules

Abstract

-Synuclein (Syn) aggregation via liquid-liquid phase separation has recently emerged as a crucial mechanism underlying amyloid fibril formation implicated in Parkinsons disease. However, comprehensive investigations of the physico-chemical properties of Syn condensate remains incomplete. Here, we showed that Syn condensate possesses a highly negative electrostatic potential that spans the whole condensate. This property causes differential partitioning of dye-labeled Syn as well as fluorescent molecules by an order of magnitude depending on their net charges. Consistent with this, the phase separation propensity of Syn is governed by a delicate balance between self-association of Syn and electrostatic repulsion, hence is antagonized by excess negative charge. We further demonstrated that, in differentiated neuron-like SH-SY5Y cells, Syn also forms negatively charged condensate. Our results highlighted the significant impact of Syn condensates electrostatic potential on molecular partitioning, hence calling for close examination of the electrostatic property of other biomolecular condensates.