The tyrosine kinase inhibitor STI571 induces cellular clearance of PrPSc in prion-infected cells.
The conversion of the cellular prion protein (PrP(c)) into pathologic PrP(Sc) and the accumulation of aggregated PrP(Sc) 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 approximately 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 PrP(Sc) propagation, with an IC(50) of < or =1 microM. STI571 cleared prion-infected cells in a time- and dose-dependent manner from PrP(Sc) without influencing biogenesis, localization, or biochemical features of PrP(c). Interestingly, this compound did not interfere with the de novo formation of PrP(Sc) but activated the lysosomal degradation of pre-existing PrP(Sc), lowering the half-life of PrP(Sc) from > or =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 PrP(Sc) and that substances specifically interfering with cellular signaling pathways might represent a novel class of anti-prion compounds.
Ertmer
Alexa
A
Institute of Virology, Prion Research Group, Technical University of Munich, Biedersteiner Strasse 29, D-80802 Munich, Germany.
Gilch
Sabine
S
Yun
Seong-Wook
SW
Flechsig
Eckhard
E
Klebl
Bert
B
Stein-Gerlach
Matthias
M
Klein
Michael A
MA
Schätzl
Hermann M
HM
D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects*; D017096:Prion Diseases / Q000188:drug therapy / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D018620:PrPSc Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl