Prion disease is delayed in mice overexpressing sortilin following prion infection

Abstract

Conformational conversion of the cellular isoform of prion protein, designated PrP C , into the abnormally folded, amyloidogenic isoform, PrP Sc , plays a key pathogenic role in prion diseases, including Creutzfeldt-Jacob disease in humans. We previously reported that sortilin, a member of the vacuolar protein sorting 10 protein (VPS10P) domain receptor family, could play a protective role in prion disease by functioning as a cargo receptor that delivers PrP C and PrP Sc to lysosomes for degradation. In this study, we generated transgenic mice overexpressing sortilin, termed TgSortilin mice, and intracerebrally inoculated them and control mice with various mouse-adapted prion strains. TgSortilin mice exhibited lower PrP C levels in their brains, although PrP mRNA levels were comparable between TgSortilin and control mice, suggesting that sortilin overexpression reduces PrP C levels, probably through lysosomal degradation of PrP C . Consistent with this, TgSortilin mice showed reduced susceptibility to prion infection. They eventually developed prion disease after inoculation, but with prolonged incubation times and lower brain accumulation of PrP Sc , to varying degrees depending on the inoculated prion strains. These findings indicate that sortilin overexpression lowers PrP C levels and thereby delays prion pathogenesis, suggesting that sortilin-mediated PrP C degradation may be a potential therapeutic target in prion diseases.