NR ATII
AU Löfgren,K.M.; Cheng,F.; Fransson,L.A.; Mani,K.; Bedecs,K.
TI The Involvement of Glypican-1 in Prion Formation
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-40
PT Konferenz-Poster
AB
Conversion of the cellular prion protein (PrPc), to the disease-causing isoform (PrPsc), is believed to occur during endocytosis and/or recycling of PrPc. Still little is known about the molecular and cellular mechanisms that lead to this conformational change, however the requirement of cellular cofactors have been suggested. Several lines of evidence have shown sulfated glycosaminoglycans, like heparan sulfate (HS) to be physiological ligands of PrPc and that a cellular heparan sulfate participates in the metabolism of prions. However, which HS proteoglycan (HSPG) is involved in PrPsc formation remains to be determined.
One such candidate HSPG is the glycosylphosphatidylinositol (GPI)-anchored glypican-1 (Gpc-1) which is particularly expressed in the adult brain.
Although the function of Gpc-1 is not well known, recent studies have shown that Gpc-1 is a potent vehicle for polyamine uptake in mammalian cells. The Gpc-1 core protein can be S-nitrosylated and when NO is released from these sites in a reducing compartment, possibly endosomes, the HS chains can be cleaved at N-unsubstituted sites, releasing the bound cargo from Gpc-1. Both the S-nitrosylation and the release of NO from Gpc-1 are supported by PrPc.
In this study we have characterized the role of Gpc-1 in the conversion of PrPc to PrPsc, as well as the importance of Gpc-1 recycling and NO-dependent degradation of HS in PrPsc formation. In scrapie-infected cells (ScGT1), Gpc-1 assumes a punctuate distribution, in contrast to the even distribution in uninfected cells. Additionally, the NO-catalyzed HS degradation in Gpc-1 is increased, whereas the heparanase-dependent HS cleavage is decreased in ScGT1 cells. Understanding the involvement of HSPG in general and Gpc-1 in particular in prion formation is of major importance as these studies can provide a basis for therapeutic and prophylactic reagents of prion diseases.
AD K.M.Lofgren, K.Bedecs, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden; F.Cheng, L.-Å.Fransson, K.Mani, Department of Experimental Medical Sience, Division of Neuroscience, Lund University, Biomedical center C13, Lund, Sweden
SP englisch
PO Deutschland