title: Age-related oxidative modifications of transthyretin modulate its amyloidogenicity.
abstract: The transthyretin amyloidoses are diseases of protein misfolding characterized by the extracellular deposition of fibrils and other aggregates of the homotetrameric protein transthyretin (TTR) in peripheral nerves, heart, and other tissues. Age is the major risk factor for the development of these diseases. We hypothesized that an age-associated increase in the level of protein oxidation could be involved in the onset of the senile forms of the TTR amyloidoses. To test this hypothesis, we have produced and characterized relevant age-related oxidative modifications of the wild type (WT) and the Val122Ile (V122I) TTR variant, both involved in cardiac TTR deposition in the elderly. Our studies show that methionine/cysteine-oxidized TTR and carbonylated TTR from either the WT or the V122I variant are thermodynamically less stable than their nonoxidized counterparts. Moreover, carbonylated WT and carbonylated V122I TTR have a stronger propensity to form aggregates and fibrils than WT and V122I TTR, respectively, at physiologically attainable pH values. It is well-known that TTR tetramer dissociation, the limiting step for aggregation and amyloid fibril formation, can be prevented by small molecules that bind the TTR tetramer interface. Here, we report that carbonylated WT TTR is less amenable to resveratrol-mediated tetramer stabilization than WT TTR. All the oxidized forms of TTR tested are cytotoxic to a human cardiomyocyte cell line known to be a target for cardiac-specific TTR variants. Overall, these studies demonstrate that age-related oxidative modifications of TTR can contribute to the onset of the senile forms of the TTR amyloidoses.
authors: Department of Molecular and Experimental Medicine, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors: Lei
authors: L
authors: Zhao
authors: Joel N
authors: JN
authors: Buxbaum
authors: Natàlia
authors: N
authors: Reixach
mesh_terms: D000367:Age Factors; D000375:Aging; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000686:Amyloidosis / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D052160:Benzothiazoles; D002460:Cell Line; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D017354:Point Mutation; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D050050:Protein Carbonylation; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D013844:Thiazoles / Q000378:metabolism
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D011228:Prealbumin; D011994:Recombinant Proteins; D013267:Stilbenes; D013844:Thiazoles; C009462:thioflavin T; D000077185:Resveratrol