Inhibition of the FKBP family of peptidyl prolyl isomerases induces abortive translocation and degradation of the cellular prion protein

Molecular Biology of the Cell
Pawel StockiDavid B Williams

Abstract

Prion diseases are fatal neurodegenerative disorders for which there is no effective treatment. Because the cellular prion protein (PrP(C)) is required for propagation of the infectious scrapie form of the protein, one therapeutic strategy is to reduce PrP(C) expression. Recently FK506, an inhibitor of the FKBP family of peptidyl prolyl isomerases, was shown to increase survival in animal models of prion disease, with proposed mechanisms including calcineurin inhibition, induction of autophagy, and reduced PrP(C) expression. We show that FK506 treatment results in a profound reduction in PrP(C) expression due to a defect in the translocation of PrP(C) into the endoplasmic reticulum with subsequent degradation by the proteasome. These phenotypes could be bypassed by replacing the PrP(C) signal sequence with that of prolactin or osteopontin. In mouse cells, depletion of ER luminal FKBP10 was almost as potent as FK506 in attenuating expression of PrP(C). However, this occurred at a later stage, after translocation of PrP(C) into the ER. Both FK506 treatment and FKBP10 depletion were effective in reducing PrP(Sc) propagation in cell models. These findings show the involvement of FKBP proteins at different stages of PrP(C) biogenesi...Continue Reading

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Citations

Apr 10, 2016·Brain Research·Charles E Mays, Claudio Soto
Jul 14, 2016·Journal of Medicinal Chemistry·Bryan M Dunyak, Jason E Gestwicki
Feb 7, 2021·Cell Stress & Chaperones·Jennifer AbramsJason E Gestwicki
Sep 13, 2020·Acta Neuropathologica·Luke C DabinEmmanuelle Viré
Dec 11, 2021·Journal of Cellular and Molecular Medicine·Xueqing HuHongqi Ren

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Methods Mentioned

BETA
glycosylation
flow cytometry
PCR
scraping
reverse transcription PCR

Software Mentioned

FlowJo
ImageJ
Quantity One

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