NR AWPR
AU Vana,K.; Ludewigs,H.; Weiss,S.
TI A trans-dominant negative 37kDa/67kDa laminin receptor mutant as a potential therapeutic tool for the treatment of TSEs
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions THE-21
PT Konferenz-Poster
AB Prion diseases are a group of rare, fatal neurodegenerative diseases that affect both animals and humans. TSEs are usually rapidly progressive and clinical symptoms comprise dementia and loss of movement coordination, common hallmarks of TSEs is the accumulation of an abnormal isoform (PrPsc) of the host-encoded prion protein (PrPc) in the brains of affected individual. The discovery that the 37kDa/67kDa laminin receptor (LRP/LR) acts as the cell surface receptor for the cellular (PrPc) (1) and infectious prion protein (PrPsc) (2,3) opened a new perspective for the development of an anti-prion therapy. In vitro studies using an N-terminally truncated LRP mutant, representing the extracellular domain of LRP/LR (LRP102-295::FLAG), revealed a reduced binding of (i) recombinant cellular PrP to mouse neuroblastoma cells, (ii) infectious moPrP 27-30 to BHK21 cells and (iii) interfered with the PrPsc propagation in chronically scrapie-infected mouse neuroblastoma cells (4). A cell free binding assay demonstrated the direct binding of the LRP102-295::FLAG mutant to both PrPc and PrPsc (4). The secreted LRP102-295::FLAG mutant may act in a trans-dominant negative manner as a decoy by trapping PrP molecules (4). In order to test the therapeutic potential of the LRP mutant in vivo transgenic animals were generated expressing LRP102-295::FLAG ectopically in the brain. Transgenic animals showed no phenotype and transgene expression was detected in cortical and cerebellar brain regions. An intracerebral prion inoculation of these mice will prove, if the expression of the LRP102-295::FLAG mutant will impair the PrPsc accumulation in the brain and delay or prevent a manifestation of a prion disease. Thus, the LRP mutant might represent an alternative therapeutic tool for the treatment of TSEs. (1) Gauczynski et al. (2001) EMBO J. 20, 5863-5875. (2) Morel et al. (2005) Am. J. Path., 167, 10331042 (2005). (3) Gauczynski et al., (2006) J. infect. Dis. in press. (4) Vana & Weiss (2006) J. Mol. Biol. 358, 57-66.
AD K. Vana, H. Ludewigs, S. Weiss: Genzentrum - Institut für Biochemie der LMU München, Feodor-Lynen-Str. 25, D-81377 Munich, Germany; G. Mitteregger: Zentrum für Neuropathologie und Prionforschung der LMU München, Feodor-Lynen-Str. 23, 81377 München, Germany; E-mail: weiss@lmb.uni-muenchen.de
SP englisch
PO Italien