Formation of cytotoxic transthyretin is not dependent on inter-molecular disulphide bridges commonly found within the amyloid form
2008 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, Vol. 15, no 4, 240-245 p.Article in journal (Refereed) Published
Familial amyloidotic polyneuropathy (FAP) is linked to destabilising point mutations in the human plasma protein transthyretin (TTR). Consistent with similar amyloid disorders, low molecular weight TTR oligomers have been shown to exert the major cytotoxic effect. The amyloid structure of TTR contains non-native inter-molecular disulphide linkages via the cysteine at position 10 (Cys10). Moreover, substitution of Cys10 in a mouse model for TTR-amyloidosis abolishes TTR deposits, indicating an important role of Cys10 in FAP pathogenesis. However, the role of disulphide bridges in TTR cytotoxicity has not been elucidated. By probing Cys10Ser TTR variants to the human neuroblastoma SH-SY5Y cell line, we have addressed this question, and our results clearly show that formation of an inter-molecular disulphide bridge is not a pre-requisite for TTR cytotoxicity. This finding suggests that prevention of inter-molecular TTR disulphide bridges as a therapeutic intervention will not impair the cytotoxic potential of TTR.
Place, publisher, year, edition, pages
2008. Vol. 15, no 4, 240-245 p.
Transthyretin, familial amyloidotic polyneuropathy, disulphide bridges, cytotoxicity, oligomers
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject Biochemistry
IdentifiersURN: urn:nbn:se:umu:diva-22628DOI: 10.1080/13506120802524916PubMedID: 19065295OAI: oai:DiVA.org:umu-22628DiVA: diva2:217434