BINDING OF THE PROTEASE-SENSITIVE FORM OF PRION PROTEIN PRP TO SULFATED GLYCOSAMINOGLYCAN AND CONGO RED

Congo red and certain sulfated glycans are potent inhibitors of protea se-resistant PrP accumulation in scrapie-infected cells. One hypothesi s is that these inhibitors act by blocking the association between pro tease-resistant PrP and sulfated glycosaminoglycans or proteoglycans ( e.g., heparan sulfate proteoglycan) that is observed in amyloid plaque s of scrapie-infected brain tissue. Accordingly, we have investigated whether the apparent precursor of protease-resistant PrP, protease-sen sitive PrP, binds to Congo red and heparin, a highly sulfated glycosam inoglycan with an inhibitory potency like that of heparan sulfate. Pro tease-sensitive PrP released from the surface of mouse neuroblastoma c ells bound to heparin-agarose and Congo red-glass beads. Sucrose densi ty gradient fractionation provided evidence that at least some of the PrP capable of binding heparin-agarose was monomeric. Free Congo red b locked PrP binding to heparin and vice versa, suggesting that these li gands share a common binding site. The relative efficacies of pentosan polysulfate, Congo red, heparin, and chondroitin sulfate in blocking PrP binding to heparin-agarose corresponded with their previously demo nstrated potencies in inhibiting protease-resistant PrP accumulation. These results are consistent with the idea that sulfated glycans and C ongo red inhibit protease-resistant PrP accumulation by interfering wi th the interaction of PrP with an endogenous glycosaminoglycan or prot eoglycan.