Dimerization of the cellular prion protein inhibits propagation of scrapie prions

A central step in the pathogenesis of prion diseases is the conformational transition of the cellular prion protein (PrP^C) into the scrapie isoform, denoted PrP^Sc Studies in transgenic mice have indicated that this conversion requires a direct interaction between PrP^C and PrP^Sc; however, insights into the underlying mechanisms are still missing. Interestingly, only a subfraction of PrP^C is converted in scrapie-infected cells, suggesting that not all PrP^C species are suitable substrates for the conversion. On the basis of the observation that PrP^C can form homodimers under physiological conditions with the internal hydrophobic domain (HD) serving as a putative dimerization domain, we wondered whether PrP dimerization is involved in the formation of neurotoxic and/or infectious PrP conformers. Here, we analyzed the possible impact on dimerization of pathogenic mutations in the HD that induce a spontaneous neurodegenerative disease in transgenic mice. Similarly to wildtype (WT) PrP^C, the neurotoxic variant PrP(AV3) formed homodimers as well as heterodimers with WTPrP^C Notably, forced PrP dimerization via an intermolecular disulfide bond did not interfere with its maturation and intracellular trafficking. Covalently linked PrP dimers were complex glycosylated, GPI-anchored, and sorted to the outer leaflet of the plasma membrane. However, forced PrP^C dimerization completely blocked its conversion into PrP^Sc in chronically scrapie-infected mouse neuroblastoma cells. Moreover, PrP^C dimers had a dominant-negative inhibition effect on the conversion of monomeric PrP^C Our findings suggest that PrP^C monomers are the major substrates for PrP^Sc propagation and that it may be possible to halt prion formation by stabilizing PrP^C dimers.