Copper drives prion protein phase separation and modulates aggregation.

Abstract

Prion diseases are characterized by prion protein (PrP) transmissible aggregation and neurodegeneration, which has been linked to oxidative stress. The physiological function of PrP seems related to sequestering of redox-active Cu²⁺, and Cu²⁺ dyshomeostasis is observed in prion disease brain. It is unclear whether Cu²⁺ contributes to PrP aggregation, recently shown to be mediated by PrP condensation. This study indicates that Cu²⁺ promotes PrP condensation in live cells at the cell surface and in vitro through copartitioning. Molecularly, Cu²⁺ inhibited PrP β-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 PrP^C initially protected against Cu²⁺ cytotoxicity but led to PrP^C aggregation upon extended copper exposure. Our data suggest that PrP condensates function as a buffer for copper that prevents copper toxicity but can transition into PrP aggregation at prolonged oxidative stress.