Interaction of PrP with NRAGE, a protein involved in neuronal apoptosis

Abstract

Prion diseases involve the conversion of the endogenous prion protein, PrP C, into a disease-associated form PrP Sc. Reports show that a subset of PrP C is subject to degradation in the cytosol by the ubiquitin–proteasome system. Some studies show that cytosolic PrP C is neuroprotective, while others show that it is neurotoxic. Here, we report that cytosolic PrP C constructs interact with a pro-apoptotic protein, NRAGE (neurotrophin receptor interacting MAGE homolog). This novel interaction was identified in a yeast two-hybrid screen using PrP C as bait and confirmed by an in vitro binding assay and co-immunoprecipitations. Endogenous NRAGE accumulated in perinuclear aggregates following proteasome inhibition, and recombinant NRAGE and PrP C–EGFP co-localized in aggresomes after proteasome inhibition. Finally, co-expression of NRAGE and cytosolic PrP C affected mitochondrial membrane potential in neuroblastoma cells. Our results suggest that interaction of cytosolic PrP and NRAGE could affect neuronal viability.