NR AREL
AU Gauczynski,S.; El-Gogo,S.; Papy-Garcia,D.; Barritault,D.; Lasmezas,C.I.; Weiss,S.
TI Interference of pentosan polysulfate and heparan sulfate mimetics with the binding of the mouse scrapie prion protein to moLRP-expressing BHK cells
QU TSE-Forum, 4. Kongress - Nationale TSE-Forschungsplattform, Düsseldorf 28.10.-29.10.2004, Poster GL-20
PT Konferenz-Poster
AB
Recently, we identified the PrP interacting 37 kDa/67 kDa laminin receptor (LRP/LR) (1) as the cell surface receptor for the cellular prion protein (PrPc) (2) and heparan sulfate proteoglycans (HSPGs) as co-factors within the PrP-LRP/LR binding complex (3). Furthermore, it has been shown that LRP/LR is required for PrPsc propagation in neuronal cells (4).
Here we investigated the binding of the proteinase K-digested mouse scrapie prion protein (moPrP27-30) to mammalian cells via the Semliki-Forest-Virus system. Enhanced binding of moPrP27-30 to BHK cells was observed when moLRP::FLAG was overexpressed to the cell surface and LRP/LR specific antibodies totally blocked the binding reaction suggesting that LRP/LR might act as a receptor for PrPsc. Expression of recombinant moPrP to the cell surface also increased the binding of moPrP27-30 deducing that PrPc might contribute to the cell binding of its infectious counterpart.
Sulfated glycans such as pentosan polysulfate (SP54) and synthetic heparan sulfate mimetics (HMs) have a therapeutic and prophylactic potential in TSEs (5-7). Here we show the inhibitory effect of SP54, its derivative PS3, HM5004 and HM2602 on the binding of moPrP27-30 to moLRP::FLAG expressing BHK cells suggesting that these substances might interfere with scrapie prion propagation by blocking the moPrP27-30-LRP/LR interaction on the cell surface. Here HMs might act as competitors of endogenous heparan sulfates known as co-receptors for the binding of PrPc to its receptor LRP/LR. Since HMs revealed a higher anti-prion potential than SP54 and PS3, they represent promising reagents for the treatment of TSEs.
1. Rieger, R. et al. (1997) Nat Med, 3, 1383-8.
2. Gauczynski, S. et al. (2001) EMBO J, 20, 5863-75.
3. Hundt, C. et al. (2001) EMBO J, 20, 5876-86.
4. Leucht, C. et al. (2003) EMBO Rep 4, 290-5.
5. Farquhar, C. et al. (1999) Lancet, 353, 117-24
6. Adjou, K. T. et al. (2003) J Gen Virol, 84, 2595-603
7. Schonberger, O. et al. (2003) BBRC, 312, 473-9
AD Sabine Gauczynski, Susanne El-Gogo, and Stefan Weiss, Laboratorium für Molekulare Biologie - Genzentrum-Institut für Biochemie der LMU München, Feodor-Lynen-Str. 25, 81377 München, Germany; Dulce Papy-Garcia, Denis Barritault, Laboratoire CRRET/CNRS FRE 2412, Université Paris XII-Val de Marne, Avenue du Général de Gaulle, 94010 Créteil Cedex, France; Corinne 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
OR Tagungsband