The adhesion GPCR Adgrd1 is a prion protein receptor and a mediator of prion cytotoxicity

Abstract

AbstractIn prion diseases, the cellular prion protein PrPCis converted into aggregates of PrPSc, leading to profound neurotoxicity through largely unknown mechanisms. Here we report that the cellular prion protein PrPCacts as an antagonist of the adhesion G protein-coupled receptor (GPCR) Adgrd1. When overexpressed in cultured cells, Adgrd1 recruited the G-protein Gαs, inducing excessive cytosolic cAMP, growth arrest and cytotoxicity, all of which were suppressed by FT25-50, a 26-meric peptide from the N-terminal flexible tail (FT) of PrPC. We found that FT25-50forms a complex with Adgrd1 and suppresses its intrinsic activation by the Stachel peptide. Adgrd1 ablation attenuated the neurodegeneration of prion-infected cerebellar organotypic slice cultures and prolonged the healthspan of prion-infected mice. Interaction studies with mutated proteins, computational modeling and docking studies revealed that suppression of Adgrd1 signaling requires the polybasic domain of the FT and the N-terminal fragment of Adgrd1. In the absence of PrPC, the cAMP spike caused by Adgrd1 was suppressed by co-expression of a functionally dead Adgrd1-Adgrg6 chimeric receptor, suggesting that Adgrd1 activation requires an unidentified agonistic ligand displaced by FT25-50. These results identify Adgrd1 as a mediator of prion toxicity and suggest that Adgrd1 modulators may be beneficial against prion-related neurodegeneration.