FK506 inhibits the FKBP family of peptidyl prolyl isomerases and results in abortive translocation and degradation of the cellular prion protein. Depletion of one FKBP, FKBP10, results in degradation of PrPC following its translocation into the ER.
Prion disease occurs when the normal cellular prion protein (PrPC) is misfolded by a pathogenic form of the protein termed PrP scrapie (PrPSc). One approach to treat prion diseases is to reduce or eliminate PrPC since mice lacking this protein show few ill effects. The human-approved immunosuppressive drug FK506 has been shown to extend survival in prion infected mice but the mechanism has been controversial. In a paper published in the March 1st issue of Molecular Biology of the Cell and featured in the online blog ASCB Post the Williams lab showed that FK506 treatment of mouse or human cells causes a profound reduction in the level of PrPC, an effect that they traced to defective translocation of PrPC into the lumen of the endoplasmic reticulum. The mislocalized PrPC is then degraded in the cytosol by the proteasome. In collaboration with the Westaway lab at U. Alberta, FK506 was also shown to be effective in depleting PrPSc in scrapie-infected cells. Since FK506 inhibits the FKBP family of peptidyl prolyl isomerases, follow-up experiments focused on these enzymes and revealed the involvement of FKBP family members in PrPC biogenesis both during and following translocation. Consequently, FKBP proteins constitute attractive targets in developing new treatments for prion diseases.
