Date Published: June 30, 2017
Publisher: Public Library of Science
Author(s): Keiji Uchiyama, Mitsuru Tomita, Masashi Yano, Junji Chida, Hideyuki Hara, Nandita Rani Das, Anders Nykjaer, Suehiro Sakaguchi, Neil A. Mabbott.
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 PrPSc is progressively accumulated in prion-infected neurons remains unknown. Here, we show that PrPSc is progressively accumulated in prion-infected cells through degradation of the VPS10P sorting receptor sortilin. We first show that sortilin interacts with PrPC and PrPSc and sorts them to lysosomes for degradation. Consistently, sortilin-knockdown increased PrPSc accumulation in prion-infected cells. In contrast, overexpression of sortilin reduced PrPSc accumulation in prion-infected cells. These results indicate that sortilin negatively regulates PrPSc accumulation in prion-infected cells. The negative role of sortilin in PrPSc accumulation was further confirmed in sortilin-knockout mice infected with prions. The infected mice had accelerated prion disease with early accumulation of PrPSc 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 PrPSc becoming detectable in cells after infection with prions. These results indicate that PrPSc accumulation stimulates sortilin degradation in lysosomes. Taken together, these results show that PrPSc accumulation of itself could impair the sortilin-mediated sorting of PrPC and PrPSc to lysosomes for degradation by stimulating lysosomal degradation of sortilin, eventually leading to progressive accumulation of PrPSc in prion-infected cells.
Prion diseases are a group of fatal neurodegenerative disorders, which include Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy and scrapie in animals . They are caused by the infectious agents termed prions, which mainly consist of the abnormally folded, amyloidogenic isoform of prion protein, designated PrPSc. PrPSc is a β-sheet-rich conformer produced by conformational conversion of the cellular counterpart, PrPC . Intermolecular interaction between PrPC and PrPSc is essential for the conversion of PrPC into PrPSc. We and others have shown that mice devoid of PrPC neither developed the disease nor accumulated PrPSc even after prions were inoculated into their brains [2–5]. These results indicate that the conversion of PrPC into PrPSc plays a pivotal role in the pathogenesis of prion disease, and that depletion of PrPC could be therapeutic by preventing the production of PrPSc.
In the present study, we showed that PrPSc accumulation could be enhanced through PrPSc-stimulated degradation of sortilin, a member of the VPS10P sorting receptor family. Sortilin functions as a negative regulator for PrPSc accumulation by sorting PrPC and PrPSc to the late endosome/lysosome protein degradation pathway. However, PrPSc stimulates sortilin to be degraded in lysosomes, thereby disturbing the inhibitory role of sortilin and eventually leading to the further accumulation of PrPSc.