Soluble Dimeric Prion Protein Binds PrPSc In Vivo and Antagonizes Prion Disease

Conversion of cellular prion protein (PrPC) into a pathological conformer (PrPSc) is thought to be promoted by PrPSc in a poorly understood process. Here, we report that in wild-type mice, the expression of PrPC rendered soluble and dimeric by fusion to immunoglobulin Fcγ (PrP-Fc2) delays PrPSc accumulation, agent replication, and onset of disease following inoculation with infective prions. In infected PrP-expressing brains, PrP-Fc2 relocates to lipid rafts and associates with PrPSc without acquiring protease resistance, indicating that PrP-Fc2 resists conversion. Accordingly, mice expressing PrP-Fc2 but lacking endogenous PrPC are resistant to scrapie, do not accumulate PrP-Fc2Sc, and do not transmit disease to others. These results indicate that various PrP isoforms engage in a complex in vivo, whose distortion by PrP-Fc2 affects prion propagation and scrapie pathogenesis. The unique properties of PrP-Fc2 suggest that soluble PrP derivatives may represent a new class of prion replication antagonists.