Sulfated glycans stimulate endocytosis of the cellular isoform of the prion protein, PrPC, in cultured cells.
There is currently no effective therapy for human prion diseases. However, several polyanionic glycans, including pentosan sulfate and dextran sulfate, prolong the incubation time of scrapie in rodents, and inhibit the production of the scrapie isoform of the prion protein (PrPSc), the major component of infectious prions, in cultured neuroblastoma cells. We report here that pentosan sulfate and related compounds rapidly and dramatically reduce the amount of PrPC, the non-infectious precursor of PrPSc, present on the cell surface. This effect results primarily from the ability of these agents to stimulate endocytosis of PrPC, thereby causing a redistribution of the protein from the plasma membrane to the cell interior. Pentosan sulfate also causes a change in the ultrastructural localization of PrPC, such that a portion of the protein molecules are shifted into late endosomes and/or lysosomes. In addition, we demonstrate, using PrP-containing bacterial fusion proteins, that cultured cells express saturable and specific surface binding sites for PrP, many of which are glycosaminoglycan molecules. Our results raise the possibility that sulfated glycans inhibit prion production by altering the cellular localization of PrPC precursor, and they indicate that endogenous proteoglycans are likely to play an important role in the cellular metabolism of both PrPC and PrPSc.
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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Shyng
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Lehmann
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Moulder
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Harris
D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D017931:DNA Primers; D016264:Dextran Sulfate / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D009447:Neuroblastoma; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology; D010430:Pentosyltransferases / Q000378:metabolism; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011134:Polysaccharides / Q000494:pharmacology*; D018621:PrPC Proteins / Q000032:analysis / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000378:metabolism; D013464:Sulfuric Acids / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D000097608:UDP Xylose-Protein Xylosyltransferase
D017931:DNA Primers; D016264:Dextran Sulfate; D010426:Pentosan Sulfuric Polyester; D010430:Pentosyltransferases; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D010727:Phosphoric Diester Hydrolases; D011134:Polysaccharides; D018621:PrPC Proteins; D011993:Recombinant Fusion Proteins; D013464:Sulfuric Acids; D000097608:UDP Xylose-Protein Xylosyltransferase