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Molecular and cellular studies of transthyretin and related amyloid pathogenesis

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Thesis type
(Dissertation) Ph.D.
Date created
Transthyretin (TTR) is a tetrameric protein involved in the extracellular transport of various compounds including thyroid hormones and retinol (vitamin A). Misfolded and aggregated TTRs (agTTR) contribute to amyloidogenic diseases such as senile systemic amyloidosis and familial amyloid polyneuropathy which are characterized by extracellular deposition of transthyretin-containing amyloid fibrils. The main objective of this thesis project was to examine the cellular toxicity of agTTR as it relates to amyloidogenic disease. Novel evidence is provided—through multiple biochemical and cellular experimental strategies—for disruption of cell membrane structure and function, and induction of oxidative stress, by agTTR relative to normal TTR or non-TTR controls. Cells treated with agTTR had a decreased capacity to bind filipin and were deficient in receptor-mediated endocytosis of the circulatory iron-carrier protein, transferrin (Tf). Increased levels of pro-oxidative species including hydrogen peroxide and nitrite, and lower levels of antioxidant factor such as glutathione and catalase, were detected upon agTTR treatement of different human cell lines. Cytosolic fractions of cells treated with agTTR exhibited decreased total antioxidant potential; and such a decrease could be moderated by redox modulators such as apocynin and NG-monomethyl-L-arginine. Hypotheses were also proposed and tested in relation to more basic physiological studies of TTR cellular receptors and endocytic transport. Biochemical evidence is provided for a TTR endocytic pathway that is different from the well-established clathrin-mediated endocytosis of Tf, and likely represents a caveolar endocytic pathway. Moreover, through chemical crossslinking and ligand blotting experiments, evidence was obtained for a novel somatic cell membrane TTR receptor.
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Scholarly level
Supervisor or Senior Supervisor
Thesis advisor: Vieira, Amandio
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