Familial Creutzfeldt-Jakob disease (CJD) comprises a group of neurodegenerative disorders for which currently there is no treatment. In this study, we evaluated the efficacy of drugs approved for human use, and protein folding agents in reversing the mutant phenotype of familial CJD H187R in a cell model. For an efficient experimental readout, green fluorescent protein (GFP)-tagged mutant prion protein (PrP(187R-GFP)) and wild-type PrP (PrP(C-GFP)) were expressed in human neuroblastoma cells. We report that unlike PrP(C-GFP) that is expressed on the cell surface, PrP(187R-GFP) accumulates in the lysosomes of transfected cells. Treatment of PrP(187R-GFP) cells with quinacrine or doxycycline, agents known to inhibit the replication of PrP-scrapie (PrP(Sc)) in experimental models, gave conflicting results; doxycycline reverted the mutant phenotype of PrP(187R-GFP) cells, whereas quinacrine had no effect. The concentration of doxycycline used in these studies is well within the plasma concentration of patients receiving a 250-600 mg dose two to three times daily. Interestingly, exposure of PrP(187R-GFP) cells to low temperature (28 degrees C) or to the chemical chaperones dimethyl sulphoxide (DMSO) and glycerol also reversed the mutant phenotype. These data suggest that doxycycline and protein folding agents may hold promise as therapeutic agents for familial CJD H187R and other familial disorders that share similar pathogenic mechanisms.