Targeting prion proteins in neurodegenerative disease.

BACKGROUND: Spongiform neurodegeneration is the pathological hallmark of individuals suffering from prion disease. These disorders, whose manifestation is sporadic, familial or acquired by infection, are caused by accumulation of the aberrantly folded isoform of the cellular prion protein (PrP(c)), termed PrP(Sc). Although usually rare, prion disorders are inevitably fatal and transferrable by infection. OBJECTIVE: Pathology is restricted to the central nervous system and premortem diagnosis is usually not possible. Yet, promising approaches towards developing therapeutic regimens have been made recently. METHODS: The biology of prion proteins and current models of neurotoxicity are discussed and prophylactic and therapeutic concepts are introduced. RESULTS/CONCLUSIONS: Although various promising drug candidates with antiprion activity have been identified, this proof-of-concept cannot be transferred into translational medicine yet.

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.