Identification of drugs that enhance the stimulatory effect of PrP on the fibrinolytic system
Guido Epple, Gerhard Kettelgerdes, Ute Mueller, Reinhard Geßner and Michael Praus
Institute of Laboratory Medicine and Biochemistry, Charite
Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany <e-mail> [email protected]
Abstract
Introduction
Both, the disease-associated isoform of the prion protein (PrP^""), and the cellular form (PrP^) bind to plasminogen. PrP^ and the NH2-terminal part spanning amino acids 23-110 (PrP23-110) can stimulate tissue-type plas- minogen activator (t-PA) mediated plasmin generation. We have shown that the lysine dependent binding of PrP23-l 10 to the kringle 2-domain of t-PA is essential for this activation. We have also shown that the stimu- latory activity of PrP23-l 10 can be enhanced by proteoglycans, which alter the self-binding of the PrP-fragment. The goal of our current study was to find additional drugs exhibiting the same effect.
Methods
Plasminogen activation was measured in a chromogenic assay in vitro and binding studies were carried out using surface plasmon resonance tech- nology.
Results
We measured the t-PA mediated plasminogen activation by PrP and the selfbinding of PrP23-110 in the presence of different potential anti-prion drugs. The strongest stimulatory effect was observed for Pentosan poly- sulfate which has already been used as an experimental drug for the treat- ment of vCJD.
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sulfate which has already been used as an experimental drug for the treat- ment of vCJD.
Conclusions
The specific stimulation of t-PA mediated plasminogen activation by PrP suggests a biological function of PrP as a cofactor in the regulation of plasmin activity in the central nervous system. Stimulation of the fibri- nolytic system is a possible new approach for the therapy of prion-diseases. The in-vitro plasminogen activation assay can be used to screen for compounds exhibiting such an effect.
This work was supported by the German Ministry of Education and Re- search (BMBF).
