NR ATHM
AU Ertmer,A.; Gilch,S.; Flechsig,E.; Schätzl,H.M.
TI Inhibition of c-Abl-expression by siRNA leads to a reduction of PrPsc in prion-infected neuroblastoma cells.
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Cell Biology of PrPc and PrPsc CELL-18
PT Konferenz-Poster
AB In the recent past many efforts have been done in order to interfere with prion conversion. In line with this many substances that reduce PrPsc in cell culture were identified. Recently, we reported that the tyrosin-kinase inhibitor STI571 clears prion-infected cells from PrPsc without any effect on the cellular isoform PrPc (Ertmer et al., 2004). The clearance showed to be irreversible and even after the removal of STI571 PrPsc did not reappear. This was mainly due to the fact that STI571 did not inhibit the de novo synthesis of PrPsc but activated the cellular degradation of pre-existing PrPsc. STI571 is a highly specific anti-cancer drug, which inhibits the kinases c-Kit, the PDGF-receptor and c-Abl. In our studies we could show that inhibition of c-Kit and the PDGF-receptor had no effect on PrPsc. In contrast, the abrogation of c-Abl-activity by transfection of a transdominant-negative c-Abl-mutant led to a slight reduction of PrPsc in prion-infected ScN2a-cells. In this context, we inhibited c-Abl-expression in ScN2a-cells by transfection of siRNA-expression plasmids. Here we show that the down-regulation of c-Abl in fact reduced PrPsc in ScN2a-cells. The effect was specific as expression of a random-siRNA had no effect on PrPsc. These studies strengthen our previous observation that the clearance of prion-infected ScN2a-cells from PrPsc by the treatment with STI571 is due to the inhibition of c-Abl. Investigations in order to identify the signalling pathway responsible for the observed anti-prion effect will be useful in understanding the cellular processes of prion conversion and clearance of PrPsc.
AD A.Ertmer, S.Gilch, H.M.Schätzl, Technichal University of Munich, Germany; E.Flechsig, University of Würzburg, Germany
SP englisch
PO Deutschland