Document Detail


Age-related oxidative modifications of transthyretin modulate its amyloidogenicity.
MedLine Citation:
PMID:  23414091     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Lei Zhao; Joel N Buxbaum; Natàlia Reixach
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-03-04
Journal Detail:
Title:  Biochemistry     Volume:  52     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-19     Completed Date:  2013-05-09     Revised Date:  2014-03-26    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1913-26     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Age Factors
Aging
Amyloid / chemistry*,  genetics,  metabolism*,  toxicity
Amyloidosis / epidemiology,  genetics,  metabolism*,  pathology
Cell Line
Humans
Myocytes, Cardiac / metabolism,  pathology
Oxidation-Reduction
Point Mutation
Prealbumin / chemistry*,  genetics,  metabolism*,  toxicity
Protein Carbonylation
Protein Multimerization / drug effects
Protein Structure, Secondary
Protein Structure, Tertiary
Recombinant Proteins / chemistry,  genetics,  metabolism,  toxicity
Stilbenes / pharmacology
Thiazoles / metabolism
Grant Support
ID/Acronym/Agency:
AG032285/AG/NIA NIH HHS; R01 AG032285/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Amyloid; 0/Prealbumin; 0/Recombinant Proteins; 0/Stilbenes; 0/Thiazoles; 2390-54-7/thioflavin T; Q369O8926L/resveratrol
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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