{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,9,8]],"date-time":"2024-09-08T09:43:07Z","timestamp":1725788587067},"reference-count":0,"publisher":"Portland Press Ltd.","issue":"4","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,8,1]]},"abstract":"<jats:p>Interactions between normal, protease-sensitive prion protein (PrP-sen or PrPc) and its protease-resistant isoform (PrP-res or PrPsc) are critical in transmissible spongiform encephalopathy (TSE) diseases. To investigate the propagation of PrP-res between cells we tested whether PrP-res in scrapie brain microsomes can induce the conversion of PrP-sen to PrP-res 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 PrP-res 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 PrP-res formation, supporting the idea that endogenous sulphated glycosaminoglycans can act as important cofactors or modulators of PrP-res formation in vivo. In an effort to develop therapeutics, the antimalarial drug quinacrine was identified as an inhibitor of PrP-res 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. PrP-res 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 PrP-res. Disruption of those interactions with antibodies or peptidomimetic drugs may be an attractive therapeutic strategy. The likelihood that PrP-res inhibitors can rid TSE-infected tissues of PrP-res would presumably be enhanced if PrP-res formation were reversible. However, our attempts to measure dissociation of PrP-sen from PrP-res have failed under non-denaturing conditions. Finally, we have attempted to induce the spontaneous conversion of PrP-sen into PrP-res using low concentrations of detergents. A conformational conversion from \u03b1-helical monomers into high-\u03b2-sheet aggregates and fibrils was induced by low concentrations of the detergent sarkosyl; however, the aggregates had neither infectivity nor the characteristic protease-resistance of PrP-res.<\/jats:p>","DOI":"10.1042\/bst0300565","type":"journal-article","created":{"date-parts":[[2004,6,24]],"date-time":"2004-06-24T09:39:54Z","timestamp":1088069994000},"page":"565-569","update-policy":"http:\/\/dx.doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Factors affecting interactions between prion protein isoforms"],"prefix":"10.1042","volume":"30","author":[{"given":"B.","family":"Caughey","sequence":"first","affiliation":[{"name":"National Institutes of Health, NIAID, Rocky Mountain Labs, Hamilton, MT 59840, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G. S.","family":"Baron","sequence":"additional","affiliation":[{"name":"National Institutes of Health, NIAID, Rocky Mountain Labs, Hamilton, MT 59840, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","container-title":["Biochemical Society Transactions"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/30\/4\/565\/535458\/bst0300565.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/30\/4\/565\/535458\/bst0300565.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T21:29:49Z","timestamp":1637184589000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article\/30\/4\/565\/64726\/Factors-affecting-interactions-between-prion"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,8,1]]},"references-count":0,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2002,8,1]]}},"URL":"https:\/\/doi.org\/10.1042\/bst0300565","relation":{},"ISSN":["0300-5127","1470-8752"],"issn-type":[{"value":"0300-5127","type":"print"},{"value":"1470-8752","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,8,1]]}}}