The tyrosine kinase inhibitor STI571 induces cellular clearance of PrPSc in prion-infected cells

The conversion of the cellular prion protein (PrPc) into pathologic PrPSc and the accumulation of aggregated PrPSc are hallmarks of prion diseases. A variety of experimental approaches to interfere with prion conversion have been reported. Our interest was whether interference with intracellular signaling events has an impact on this conversion process. We screened similar to 50 prototype inhibitors of specific signaling pathways in prion-infected cells for their capacity to affect prion conversion. The tyrosine kinase inhibitor STI571 was highly effective against PrPSc propagation, with an IC50 of less than or equal to 1 muM. STI571 cleared prion-infected cells in a time- and dose-dependent manner from PrPSc without influencing biogenesis, localization, or biochemical features of PrPc. Interestingly, this compound did not interfere with the de novo formation of PrPSc but activated the lysosomal degradation of pre-existing PrPSc, lowering the half-life of PrPSc from greater than or equal to 24 h to < 9 h. Our data indicate that among the kinases known to be inhibited by STI571, c-Abl is likely responsible for the observed anti-prion effect. Taken together, we demonstrate that treatment with STI571 strongly activates the lysosomal degradation of PrPSc and that substances specifically interfering with cellular signaling pathways might represent a novel class of anti-prion compounds.