title: Inhibition of the FKBP family of peptidyl prolyl isomerases induces abortive translocation and degradation of the cellular prion protein.
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) biogenesis and identify FKBP10 as a potential therapeutic target for the treatment of prion diseases.
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Pawel
authors.initials: P
authors.lastname: Stocki
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Sawicki
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB T6G 2M8, Canada.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Mays
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Seo Jung
authors.initials: SJ
authors.lastname: Hong
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chapman
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB T6G 2M8, Canada Division of Neurology and Departments of Chemistry and Biochemistry, University of Alberta, Edmonton, AB T6G 2M8, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Westaway
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada david.williams@utoronto.ca.
authors.forename: David B
authors.initials: DB
authors.lastname: Williams
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D018621:PrPC Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012608:Scrapie / Q000188:drug therapy / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D018621:PrPC Proteins; D046988:Proteasome Endopeptidase Complex; D022021:Tacrolimus Binding Proteins; C491675:Fkbp10 protein, mouse; D016559:Tacrolimus