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Formation of cytotoxic transthyretin is not dependent on inter-molecular disulphide bridges commonly found within the amyloid form
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Division of Rheumatology Research, W.M. Keck Autoimmune Disease Center, The Scripps Research Institute, La Jolla, CA, USA.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
2008 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, Vol. 15, no 4, 240-245 p.Article in journal (Refereed) Published
Abstract [en]

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.
Keyword [en]
Transthyretin, familial amyloidotic polyneuropathy, disulphide bridges, cytotoxicity, oligomers
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:umu:diva-22628DOI: 10.1080/13506120802524916PubMedID: 19065295OAI: oai:DiVA.org:umu-22628DiVA: diva2:217434
Available from: 2009-05-14 Created: 2009-05-14 Last updated: 2012-04-13Bibliographically approved
In thesis
1. Targeting cytotoxic species in amyloid diseases
Open this publication in new window or tab >>Targeting cytotoxic species in amyloid diseases
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyloid diseases are a world-wide problem causing great human suffer and large economical costs. Although amyloid deposits, a common denominator in all amyloid disorders, are detrimental to the surrounding tissue, there is a poor correlation between total amyloid burden and clinical symptoms. Soluble oligomers are much more potent to exert a tissue damaging effect. 

Alzheimer’s disease (AD) is strongly linked to self-assembly of the amyloid-β (Aβ) peptide. Antibodies selectively targeting cytotoxic Aβ-species are useful both for understanding oligomer formation and for their therapeutic abilities. We hypothesized that the effect of avidity would compensate for a low single site affinity and be enough to selectively target oligomers. To evaluate this hypothesis, we focused on the IgM isotype having ten antigen-binding sites. In accordance with the hypothesis, the IgM isotype effectively bound oligomeric Aβ also in presence of a vast excess of its monomeric counterpart, clearly illustrating the potentiating effect of avidity. As a continuation of this work, we have shown that the avidity effect from a bivalent binding is enough to induce oligomer specificity. This finding facilitates a direct application on the clinically more useful IgG isotype, where the binding properties now can be controlled in detail. The method is general and we have, using this technique, also designed oligomer specific antibodies targeting α-synuclein.

Transthyretin (TTR) is an amyloidogenic protein involved in both hereditary and sporadic amyloidosis. The cytotoxicity of TTR is intriguing since studies have shown cytotoxic potential from oligomers, tetramers and even monomers. Elucidation of the molecular properties associated with TTR cytotoxicity is hence of interest. By preventing tetramer dissociation, TTR aggregation and TTR-induced cytotoxicity is abolished. Based on this rationale, a current therapeutic strategy is to stabilize the TTR tetramer with small molecules. The kinetic stability within the spectra of known TTR mutations spans more than three orders of magnitude. However, although the most stable mutants are inert, a poor correlation within the group of cytotoxic variants exists where the cytotoxic effect is not potentiated in proportion to their kinetic stability. Through analysis of a large spectra of TTR variants, our results indicate that TTR induced cytotoxicity requires an intermediate stability of the TTR molecule. The kinetic stability should be low enough to permit tetramer dissociation and the thermodynamic stability high enough to prevent instant aggregation and to allow formation of the cytotoxic fold. 

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2012. 63 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1494
Keyword
Alzheimer's disease, Amyloid-beta, transthyretin, FAP, amyloid, cytotoxic species, oligomers
National Category
Cell and Molecular Biology Other Basic Medicine
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-54006 (URN)978-91-7459-414-0 (ISBN)
Public defence
2012-05-04, KB3A9, KBC, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2012-04-12 Created: 2012-04-11 Last updated: 2012-04-12Bibliographically approved

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Lindhagen-Persson, MalinOlofsson, Anders

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