期刊
NEURODEGENERATIVE DISEASES
卷 11, 期 1, 页码 42-48出版社
KARGER
DOI: 10.1159/000338153
关键词
Transthyretin; Protein aggregation; Amyloidogenic diseases; Oxidative stress; Reactive nitrogen species; Redox balance; Neurotoxicity
资金
- Natural Sciences and Engineering Research Council of Canada, NSERC
- C.D. Nelson fellowship
Background and Objective: Misfolded and aggregated transthyretins (agTTR) contribute to neurodegenerative amyloid diseases such as familial amyloid polyneuropathy and senile systemic amyloidosis. The neurotoxicity mechanisms of agTTR, however, are not well understood. In the current study, the possible contribution of reactive nitrogen species (RNS) to such mechanisms was investigated by examining agTTR-mediated changes in cellular RNS levels. Methods and Results: The production of RNS was assessed through nitrate and nitrite assays in two human cell lines after exposure to agTTR (2.4 mu M pre-aggregation concentration). In both epidermoid (A431) and schwannoma (sNF94.3) cell lines, agTTR induced significant increases in RNS (p < 0.05 relative to the same concentration of normal TTR, or no-TTR controls). Redox modulators such as apocynin (1-(4-hydroxy-3- methoxy-phenyl)ethanone) and L-NMMA (N-G-monomethyl-L-arginine) were tested for their effects on RNS production. These modulators decreased RNS production in both cell lines; although the effects of L-NMMA were statistically significant only in the schwannoma cells. Moreover, cells treated with agTTR exhibited decreases in metabolic activity relative to TTR- or non-TTR-treated cells (p < 0.05) as assessed by reduction of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Conclusion: The results provide novel evidence for involvement of RNS in pro-oxidative effects of agTTR in two different human cell lines, and show that agTTR can induce more generalized changes in cellular metabolic activity. Copyright (C) 2012 S. Karger AG, Basel
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