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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.

Prions amplify through degradation of the VPS10P sorting receptor sortilin