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 prioninfected 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 sortilinknockout 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 prioninfected 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