Copper drives prion protein phase separation and modulates aggregation
Prion diseases are characterized by prion protein (PrP) transmissible aggregation and toxicity in the brain. The physiological function of PrP seems related to sequestering and internalization of redox-active Cu2+. It is unclear whether Cu2+ contributes to PrP aggregation, recently shown to be mediated by PrP condensation. We investigated the role of Cu2+ and oxidation in PrP condensation and aggregation using multiple biophysical and biochemical methods. We find that Cu2+ promotes PrP condensation at the cell surface and in vitro through co-partitioning. Molecularly, Cu2+ inhibited PrP {beta}-structure and hydrophobic residues exposure. Oxidation, induced by H2O2, triggered liquid-to-solid transition of PrP:Cu2+ condensates and promoted amyloid-like PrP aggregation. In cells, overexpression of PrPC initially protected against Cu2+ cytotoxicity but led to PrPC aggregation upon extended copper exposure. Our data suggest that PrP condensates function as a buffer for copper that prevent copper toxicity but can transition into PrP aggregation at prolonged oxidative stress.