NR AOZZ
AU Vana,K.; Gauczynski,S.; Leucht,C.; Weiss,S.
TI Laminin Receptor Decoy mutants and Small Interfering (si) RNAs directed against the 37kDa/ 67kDa Laminin Receptor as powerful tools in therapy of prion diseases
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - IV-12
PT Konferenz-Poster
AB
Transmissible spongiform encephalopathies (TSE) are neurodegenerative diseases, which include Scrapie in sheep, bovine spongiform encephalopathie (BSE) in cattle and Creutzfeldt-Jakob-disease (CJD) in humans. Prions, the causative agents of TSE, are known to interact with the cellular prion protein (PrPc) by inducing conformational changes in the prion protein (PrPsc). The 37/67 kDa laminin receptor (LRP/LR) acts as the cell surface receptor for the cellular prion protein PrPc1. Heparan sulfate proteoglycans (HSPG's) - binding partners of the prion protein2 - were identified as co-factors/ co-receptors for the binding of PrPc to LRP/LR3 (for review4). A transmembrane deletion mutant of LRP/LR (LRPdelTMD) was secreted to the medium of BHK cells transfected with recombinant Semliki-Forest-Virus (SFV) RNAs1 and prevented PrPc binding and internalization1. Secretion of the mutant from neuroblastoma cells (N2a) will also prevent PrPc and PrPsc binding and internalization. LRP/LR is essential for PrPres propagation in neuronal cells5. Therefore, expression of the mutant in scrapie-infected neuroblastoma cells (ScN2a) might lead to reduction or ablation of PrPsc propagation in these cells recommending the transmembrane deletion mutant as a powerful tool for the treatment of transmissible spongiform encephalopathies. The accumulation of PrPsc in scrapie-infected neuronal cells (ScN2a) has also been prevented by transfection with small interfering (si) RNAs specific for the LRP mRNA5. These results demonstrate the necessity of the laminin receptor (LRP/ LR) for PrPsc propagation in cultured cells and suggest, that decoy mutants as well as siRNAs directed against the LRP mRNA could be used as therapeutical tools in the treatment of TSEs.
1 Gauczynski et al., EMBO J.2001, 20, 5863-75
2 Warner et al., J.Biol.Chem., 2002, 277, 18421-18430
3 Hundt et al., EMBO J., 2001, 20, 5876-86
4 Gauczynski et al., Adv Protein Chem. 2001, 57,229-72
5 Leucht et al., EMBO reports, 2003, 4, 290-295.
AD Karen Vana, Sabine Gauczynski, Christoph Leucht, Stefan Weiss, Laboratorium für Molekulare Biologie, Institut für Biochemie, Genzentrum, München, Germany
SP englisch
PO Deutschland