NR ACJF
AU Caughey,B.W.; Baron,G.S.
TI Factors affecting interactions between prion protein isoforms
QU Biochemical Society Transactions 2002 Aug; 30(4): 565-9
PT journal article
AB Interactions between normal, protease-sensitive prion protein (PrP-sen or PrPc) and its protease-resistant isoform (PrPres or PrPsc) are critical in transmissible spongiform encephalopathy (TSE) diseases. To investigate the propagation of PrPres between cells we tested whether PrPres in scrapie brain microsomes can induce the conversion of PrP-sen to PrPres if the PrP-sen is bound to uninfected raft membranes. Surprisingly, no conversion was observed unless the microsomal and raft membranes were fused or PrP-sen was released from raft membranes. These results suggest that the propagation of infection between cells requires transfer of PrPres into the membranes of the recipient cell. To assess potential cofactors in PrP conversion, we used cell-free PrP conversion assays to show that heparan sulphate can stimulate PrPres formation, supporting the idea that endogenous sulphated glycosaminoglycans can act as important cofactors or modulators of PrPres formation in vivo. In an effort to develop therapeutics, the antimalarial drug quinacrine was identified as an inhibitor of PrPres formation in scrapie-infected cell cultures. Confirmation of the latter result by others has led to the initiation of human clinical trials as a treatment for Creutzfeldt-Jakob disease. PrPres formation can also be inhibited using a variety of other types of small molecule, specific synthetic PrP peptides, and an antiserum directed at the C-terminus of PrP-sen. The latter results help to localize the sites of interaction between PrP-sen and PrPres. Disruption of those interactions with antibodies or peptidomimetic drugs may be an attractive therapeutic strategy. The likelihood that PrPres inhibitors can rid TSE-infected tissues of PrPres would presumably be enhanced if PrPres formation were reversible. However, our attempts to measure dissociation of PrP-sen from PrPres have failed under non-denaturing conditions. Finally, we have attempted to induce the spontaneous conversion of PrP-sen into PrPres using low concentrations of detergents. A conformational conversion from alpha-helical monomers into high-beta-sheet aggregates and fibrils was induced by low concentrations of the detergent sarkosyl; however, the aggregates had neither infectivity nor the characteristic protease-resistance ofPrPres.
AD National Institutes of Health, NIAID, Rocky Mountain Labs, Hamilton, MT 59840, USA
SP englisch
PO England