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 (PrPC) is required for propagation of the infectious scrapie form of the protein, one therapeutic strategy is to reduce PrPCexpression. 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 PrPCexpression. We show that FK506 treatment results in a profound reduction in PrPCexpression due to a defect in the translocation of PrPCinto the endoplasmic reticulum with subsequent degradation by the proteasome. These phenotypes could be bypassed by replacing the PrPCsignal 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 PrPCinto the ER. Both FK506 treatment and FKBP10 depletion were effective in reducing PrPScpropagation in cell models. These findings show the involvement of FKBP proteins at different stages of PrPCbiogenesis and identify FKBP10 as a potential therapeutic target for the treatment of prion diseases.