Prions amplify through degradation of the VPS10P sorting receptor sortilin

Abstract

Prion diseases are a group of fatal neurodegenerative disorders caused by prions, which consist mainly of the abnormally folded isoform of prion protein, PrPSc. A pivotal pathogenic event in prion disease is progressive accumulation of prions, or PrPSc, in brains through constitutive conformational conversion of the cellular prion protein, PrPC, into PrPSc. However, the cellular mechanism by which PrPScis progressively accumulated in prion-infected neurons remains unknown. Here, we show that PrPScis progressively accumulated in prion-infected cells through degradation of the VPS10P sorting receptor sortilin. We first show that sortilin interacts with PrPCand PrPScand sorts them to lysosomes for degradation. Consistently, sortilin-knockdown increased PrPScaccumulation in prion-infected cells. In contrast, overexpression of sortilin reduced PrPScaccumulation in prion-infected cells. These results indicate that sortilin negatively regulates PrPScaccumulation in prion-infected cells. The negative role of sortilin in PrPScaccumulation was further confirmed in sortilin-knockout mice infected with prions. The infected mice had accelerated prion disease with early accumulation of PrPScin 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 PrPScbecoming detectable in cells after infection with prions. These results indicate that PrPScaccumulation stimulates sortilin degradation in lysosomes. Taken together, these results show that PrPScaccumulation of itself could impair the sortilin-mediated sorting of PrPCand PrPScto lysosomes for degradation by stimulating lysosomal degradation of sortilin, eventually leading to progressive accumulation of PrPScin prion-infected cells.