Prions amplify through degradation of the VPS10P sorting receptor sortilin

Prion diseases are a group of fatal neurodegenerative disorders caused by prions, which consist mainly of the abnormally folded isoform of prion protein, PrP(Sc). A pivotal pathogenic event in prion disease is progressive accumulation of prions, or PrP(Sc), in brains through constitutive conformational conversion of the cellular prion protein, PrP(C), into PrP(Sc). However, the cellular mechanism by which PrP(Sc) is progressively accumulated in prion-infected neurons remains unknown. Here, we show that PrP(Sc) is progressively accumulated in prion-infected cells through degradation of the VPS10P sorting receptor sortilin. We first show that sortilin interacts with PrP(C) and PrP(Sc) and sorts them to lysosomes for degradation. Consistently, sortilin-knockdown increased PrP(Sc) accumulation in prion-infected cells. In contrast, overexpression of sortilin reduced PrP(Sc) accumulation in prion-infected cells. These results indicate that sortilin negatively regulates PrP(Sc) accumulation in prion-infected cells. The negative role of sortilin in PrP(Sc) accumulation was further confirmed in sortilin-knockout mice infected with prions. The infected mice had accelerated prion disease with early accumulation of PrP(Sc) in their brains. Interestingly, sortilin was reduced in prion-infected cells and mouse brains. Treatment of prion-infected cells with lysosomal inhibitors, but not proteasomal inhibitors, increased the levels of sortilin. Moreover, sortilin was reduced following PrP(Sc) becoming detectable in cells after infection with prions. These results indicate that PrP(Sc) accumulation stimulates sortilin degradation in lysosomes. Taken together, these results show that PrP(Sc) accumulation of itself could impair the sortilin-mediated sorting of PrP(C) and PrP(Sc) to lysosomes for degradation by stimulating lysosomal degradation of sortilin, eventually leading to progressive accumulation of PrP(Sc) in prion-infected cells.