NR ACJX
AU Caughey,B.W.; Raymond,G.J.
TI Sulfated polyanion inhibition of scrapie-associated PrP accumulation in cultured cells
QU Journal of Virology 1993 Feb; 67(2): 643-50
PT journal article
AB The accumulation of an abnormal, protease-resistant form of the protein PrP (PrPres) in hosts with scrapie and related transmissible spongiform encephalopathies appears to be important in disease pathogenesis. To gain insight into the mechanism of PrPres accumulation and the in vivo antiscrapie activity of certain polyanions, we have studied effects of sulfated glycans on PrP metabolism in scrapie-infected neuroblastoma cells. Pentosan polysulfate, like the amyloid-binding dye Congo red, potently inhibited the accumulation of PrPres in these cells without apparent effects on the metabolism of the normal isoform. The inhibition was due primarily to prevention of new PrPres accumulation rather than destabilization of preexisting PrPres. PrPres accumulation remained depressed in the cultures after removal of the inhibitors. The activities of other sulfated glycans, nonsulfated polyanions, dextran, and DEAE-dextran were compared with those of pentosan polysulfate and Congo red. This comparison provided evidence that the density of sulfation and molecular size are factors influencing anti-PrPres activity of sulfated glycans. The relative potencies of these compounds corresponded well with their previously determined antiscrapie activities in vivo, suggesting that the prophylactic effects of sulfated polyanions may be due to inhibition of PrPres accumulation. Since PrPres amyloid is known to contain sulfated glycosaminoglycans, we reason that these inhibitors may competitively block an interaction between PrP and endogenous glycosaminoglycans that is essential for its accumulation in a protease-resistant, potentially amyloidogenic state.
IN Die für übertragbare spongiforme Encephalopathien typische Akkumulation von Prionproteinen in proteaseresistenter Form wird in kultivierten Neuroblastomazellen durch das sulfatierte Polyanion Pentosanpolysulfat und den amyloidbindenden Farbstoff Kongorot verhindert. Dabei scheint der Metabolismus der normalen Isoform des Prionproteins unbeeinflußt zu bleiben und bestehende Ablagerungen werden nicht abgebaut. Die akkumulationsunterdrückende Wirkung hält auch nach Entfernung der Inhibitoren aus dem Medium an. Diese Wirkung entspricht einem prophylaktischen Schutz gegen Scrapie bei lebenden Schafen. Die scrapietypischen Amyloide enthalten sulfatierte Glycosaminoglycane.
MH Amphotericin B/pharmacology; Animal; Carrageenan; Congo Red/pharmacology; DNA/pharmacology; Dextran Sulfate; Dose-Response Relationship, Drug; Mice; Pectins; Pentosan Sulfuric Polyester/*pharmacology; Polyglutamic Acid/pharmacology; Polymers/*pharmacology; PrPsc Proteins; Prions/*biosynthesis/drug effects; RNA/pharmacology; Scrapie/*metabolism; Tumor Cells, Cultured
AD Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute for Allergy and Infectious Diseases, Hamilton, Montana 59840.
SP englisch
PO USA