NR AKVI
AU Shyng,S.L.; Lehmann,S.; Moulder,K.L.; Harris,D.A.
TI Sulfated glycans stimulate endocytosis of the cellular isoform of the prion protein, PrPc, in cultured cells
QU The Journal of Biological Chemistry 1995 Dec 15; 270(50): 30221-9
IA http://intl.jbc.org/cgi/reprint/270/50/30221
PT journal article
AB 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.
IN Pentosansulphat und verwandte Moleküle stimulieren die Endozytose des normalen zellulären Prionproteins und reduzieren schnell und weitgehend dessen Menge auf der Zelloberfläche. Die ins Zellinnere zurückgeholten Prionproteine werden dann in späten Endosomen und/oder Lysosomen gefunden. Mit bakteriellen Prionprotein-Fusionsproteinen wurde außerdem gezeigt, dass kultivierte Zellen spezifische Prionprotein-Rezeptoren auf ihren Zelloberflächen besitzen, von denen viele Glycosaminoglycanmoleküle sein sollen.
ZR 50 Zitate
MH Animal; Base Sequence; CHO Cells; Cell Line; Cell Membrane/metabolism; Cells, Cultured; DNA Primers; Dextran Sulfate/pharmacology; Endocytosis/*drug effects; Hamsters; Human; Kinetics; Mice; Molecular Sequence Data; Neuroblastoma; Pentosan Sulfuric Polyester/pharmacology; Pentosyltransferases/metabolism; Phosphoric Diester Hydrolases/metabolism; Polymerase Chain Reaction; Polysaccharides/*pharmacology; PrPc Proteins/analysis/*metabolism; Recombinant Fusion Proteins/analysis/metabolism; Sulfuric Acids/pharmacology; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Transfection; Tumor Cells, Cultured
AD Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
SP englisch
PO USA
OR Prion-Krankheiten 7