Inhibition of the FKBP family of peptidyl prolyl isomerases induces abortive translocation and degradation of the cellular prion protein |
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| Authors: | Pawel Stocki Maxime Sawicki Charles E Mays Seo Jung Hong Daniel C Chapman David Westaway David B Williams |
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| Institution: | University of Chicago;aDepartment of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada;cDepartment of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada;bCentre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB T6G 2M8, Canada;dDivision of Neurology and Departments of Chemistry and Biochemistry, University of Alberta, Edmonton, AB T6G 2M8, Canada |
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| Abstract: | Prion diseases are fatal neurodegenerative disorders for which there is no effective treatment. Because the cellular prion protein (PrPC) is required for propagation of the infectious scrapie form of the protein, one therapeutic strategy is to reduce PrPC 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 PrPC expression. We show that FK506 treatment results in a profound reduction in PrPC expression due to a defect in the translocation of PrPC into the endoplasmic reticulum with subsequent degradation by the proteasome. These phenotypes could be bypassed by replacing the PrPC 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 PrPC. However, this occurred at a later stage, after translocation of PrPC into the ER. Both FK506 treatment and FKBP10 depletion were effective in reducing PrPSc propagation in cell models. These findings show the involvement of FKBP proteins at different stages of PrPC biogenesis and identify FKBP10 as a potential therapeutic target for the treatment of prion diseases. |
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