NR ATOE
AU Gauczynski,S.; Nikles,D.; El-Gogo,S.; Papy-Garcia,D.; Barritault,D.; Lasmezas,C.I.; Weiss,S.
TI The 37 kDa/67 kDa laminin receptor is a cellular receptor for infectious prions and is inhibited by polysulfated glycans
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Human prions, risk of blood products, and therapy HUMAN-28
PT Konferenz-Poster
AB
The 37-kDa/67-kDa laminin receptor (LRP/LR) has been shown to be a receptor for PrPc on the cell surface (1). A model for the PrP-LRP/LR binding complex involving heparan sulfate proteoglycans (HSPGs) as co-factors has been postulated (2). Since it has been shown that LRP/LR is required for PrPsc propagation in neuronal cells (3), we investigated, whether the pathogenic isoform PrPsc, utilizes also LRP/LR for cellular entry by in vitro PrPsc binding and internalization assays.
The mouse scrapie prion protein (moPrP27-30) was investigated regarding entry into BHK and N2a cells. Enhanced binding of moPrP27-30 to BHK cells was observed when moLRP::FLAG was overexpressed using the Semliki-Forest-Virus system. Upon incubation with the LRP antibody W3, cell-entry of PrPsc was blocked. PrPc overexpressed in BHK cells contributed to PrP27-30 binding.
Since sulfated glycans have a therapeutic and prophylactic potential in TSEs we tested the inhibitory effect of pentosan polysulfate (SP54), its derivative PS3 as well as the heparam mimetics (HMs) 5004 and 2602 on the binding of moPrP27-30 to moLRP::FLAG expressing BHK cells. The HM 2602 was most efficient in blocking the binding of PrP27-30 to LRP::FLAG hyperexpressing BHK cells. These polysulfated glycans might interfere with scrapie prion propagation by blocking the moPrP27-30-LRP/LR interaction on the cell surface and/or by competing with endogenous heparan sulfates. Effects of specific antibodies and soluble LRP on binding/internalization of PrPsc are further investigated in neuronal cells.
Our finding that LRP/LR plays a central role in the binding and internalization process of infectious prions was confirmed by the finding that endocytosis of the infectious bovine PrPsc is mediated by LRP/LR apically expressed in human enterocytes(4).
(1) Gauczynski et al. (2001) EMBO J. 20, 5863-5875. (2) Hundt et al. (2001) EMBO J. 20, 5876-5886. (3) Leucht et al. (2003) EMBO rep 4, 290-295. (4) Morel et al. (2005) Am J Path, in press.
AD S.Gauczynski, D.Nikles, S.El-Gogo, S.Weiss, Genzentrum-Institut für Biochemie der LMU München, Feodor-Lynen-Str. 25, 81377 München, Germany; D.Papy-Garcia, D.Barritault, Laboratoire CRRET/CNRS FRE 2412, Université Paris XII-Val de Marne, Avenue du Général de Gaulle, 94010 Créteil Cedex, France; C.I.Lasmézas, CEA Laboratory for Prion Pathogenesis, Service de Neurovirologie, DRM/DSV, 18, Route du Panorama, BP.6, F-92 265 Fontenay-aux-Roses Cedex, France
SP englisch
PO Deutschland