Novel amplification mechanism of prions through disrupting sortilin-mediated trafficking

Prion
Suehiro Sakaguchi, Keiji Uchiyama

Abstract

Conformational conversion of the cellular prion protein, PrPC, into the abnormally folded isoform of prion protein, PrPSc, which leads to marked accumulation of PrPSc in brains, is a key pathogenic event in prion diseases, a group of fatal neurodegenerative disorders caused by prions. However, the exact mechanism of PrPSc accumulation in prion-infected neurons remains unknown. We recently reported a novel cellular mechanism to support PrPSc accumulation in prion-infected neurons, in which PrPSc itself promotes its accumulation by evading the cellular inhibitory mechanism, which is newly identified in our recent study. We showed that the VPS10P sorting receptor sortilin negatively regulates PrPSc accumulation in prion-infected neurons, by interacting with PrPC and PrPSc and trafficking them to lysosomes for degradation. However, PrPSc stimulated lysosomal degradation of sortilin, disrupting the sortilin-mediated degradation of PrPC and PrPSc and eventually evoking further accumulation of PrPSc in prion-infected neurons. These findings suggest a positive feedback amplification mechanism for PrPSc accumulation in prion-infected neurons.

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Citations

Apr 25, 2018·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Shu-Yin XuXiao-Xin Yan
Jul 8, 2020·Expert Opinion on Therapeutic Targets·Arianna Colini BaldeschiGiuseppe Legname

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