Sulfated glycans and elevated temperature stimulate PrPSc-dependent cell-free formation of protease-resistant prion protein

A conformational conversion of the normal, protease-sensitive prion protein (PrP-sen or PrPC) to a protease-resistant form (PrP-res or PrPSc) is commo nly thought to be required in transmissible spongiform encephalopathies (TS Es), Endogenous sulfated glycosaminoglycans are associated with PrP-res dep osits in vivo, suggesting that they may facilitate PrP-res formation. On th e other hand, certain exogenous sulfated glycans can profoundly inhibit PrP -res accumulation and serve as prophylactic anti-TSE compounds in vivo. To investigate the seemingly paradoxical effects of sulfated glycans on PrP-re s formation, we have assayed their direct effects on PrP conversion under p hysiologically compatible cell-free conditions. Heparan sulfate and pentosa n polysulfate stimulated PrP-res formation. Conversion was stimulated furth er by increased temperature. Both elevated temperature and pentosan polysul fate promoted interspecies PrP conversion. Circular dichroism spectropolari metry measurements showed that pentosan polysulfate induced a conformationa l change in PrP-sen that may potentiate its PrP-res-induced conversion. The se results show that certain sulfated glycosaminoglycans can directly affec t the PrP conversion reaction. Therefore, depending upon the circumstances, sulfated glycans may be either cofactors or inhibitors of this apparently pathogenic process.