{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T20:33:28Z","timestamp":1778099608755,"version":"3.51.4"},"reference-count":38,"publisher":"Proceedings of the National Academy of Sciences","issue":"14","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,4,5]]},"abstract":"<jats:p>Transthyretin (TTR) is a homotetrameric protein that transports thyroxine and retinol. Tetramer destabilization and misfolding of the released monomers result in TTR aggregation, leading to its deposition as amyloid primarily in the heart and peripheral nervous system. Over 100 mutations of TTR have been linked to familial forms of TTR amyloidosis. Considerable effort has been devoted to the study of TTR aggregation of these mutants, although the majority of TTR-related amyloidosis is represented by sporadic cases due to the aggregation and deposition of the otherwise stable wild-type (WT) protein. Heparan sulfate (HS) has been found as a pertinent component in a number of amyloid deposits, suggesting its participation in amyloidogenesis. This study aimed to investigate possible roles of HS in TTR aggregation. Examination of heart tissue from an elderly cardiomyopathic patient revealed substantial accumulation of HS associated with the TTR amyloid deposits. Studies demonstrated that heparin\/HS promoted TTR fibrillization through selective interaction with a basic motif of TTR. The importance of HS for TTR fibrillization was illustrated in a cell model; TTR incubated with WT Chinese hamster ovary cells resulted in fibrillization of the protein, but not with HS-deficient cells (pgsD-677). The effect of heparin on TTR fibril formation was further demonstrated in a<jats:italic>Drosophila<\/jats:italic>model that overexpresses TTR. Heparin was colocalized with TTR deposits in the head of the flies reared on heparin-supplemented medium, whereas no heparin was detected in the nontreated flies. Heparin of low molecular weight (Klexane) did not demonstrate this effect.<\/jats:p>","DOI":"10.1073\/pnas.1101194108","type":"journal-article","created":{"date-parts":[[2011,3,22]],"date-time":"2011-03-22T05:18:24Z","timestamp":1300771104000},"page":"5584-5589","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":82,"title":["Heparan sulfate\/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein"],"prefix":"10.1073","volume":"108","author":[{"given":"Fredrik","family":"Noborn","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Husargatan 3, Box 582, 751 23 Uppsala, Sweden;"}]},{"given":"Paul","family":"O'Callaghan","sequence":"additional","affiliation":[{"name":"Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Dag Hammarskj\u00f6ldsv\u00e4g 20, 751 85 Uppsala, Sweden;"}]},{"given":"Erik","family":"Hermansson","sequence":"additional","affiliation":[{"name":"Alzheimer's Disease Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, S-141 86 Stockholm, Sweden;"}]},{"given":"Xiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Dag Hammarskj\u00f6ldsv\u00e4g 20, 751 85 Uppsala, Sweden;"}]},{"given":"John B.","family":"Ancsin","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology, The Biomedical Center, Uppsala University, Husargatan 3, Box 582, 751 23 Uppsala, Sweden;"}]},{"given":"Ana M.","family":"Damas","sequence":"additional","affiliation":[{"name":"Molecular Structure Group, Instituto de Biologia Molecular e Celular, University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal;"}]},{"given":"Ingrid","family":"Dacklin","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Ume\u00e5 University, 901 87 Ume\u00e5, Sweden;"}]},{"given":"Jenny","family":"Presto","sequence":"additional","affiliation":[{"name":"Alzheimer's Disease Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, S-141 86 Stockholm, Sweden;"}]},{"given":"Jan","family":"Johansson","sequence":"additional","affiliation":[{"name":"Alzheimer's Disease Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, S-141 86 Stockholm, Sweden;"}]},{"given":"Maria J.","family":"Saraiva","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Group, Instituto de Biologia Molecular e Celular, University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal;"}]},{"given":"Erik","family":"Lundgren","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Ume\u00e5 University, 901 87 Ume\u00e5, Sweden;"}]},{"given":"Robert","family":"Kisilevsky","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, Richardson Laboratory, 88 Stuart Street, Queen\u2019s University, Kingston, ON, Canada K7L 3N6; 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