Actin glutathionylation increases in fibroblasts of patients with Friedreich's ataxia: a potential role in the pathogenesis of the disease.
J Biol Chem
; 278(43): 42588-95, 2003 Oct 24.
Article
em En
| MEDLINE
| ID: mdl-12915401
ABSTRACT
Increasing evidence suggests that iron-mediated oxidative stress might underlie the development of neurodegeneration in Friedreich's ataxia (FRDA), an autosomal recessive ataxia caused by decreased expression of frataxin, a protein implicated in iron metabolism. In this study, we demonstrate that, in fibroblasts of patients with FRDA, the cellular redox equilibrium is shifted toward more protein-bound glutathione. Furthermore, we found that actin is glutathionylated, probably as a result of the accumulation of reactive oxygen species, generated by iron overload in the disease. Indeed, high-pressure liquid chromatography analysis of control fibroblasts in vivo treated with FeSO4 showed a significant increase in the protein-bound/free GSH ratio, and Western blot analysis indicated a relevant rise in glutathionylation. Actin glutathionylation contributes to impaired microfilament organization in FRDA fibroblasts. Rhodamine phalloidin staining revealed a disarray of actin filaments and a reduced signal of F-actin fluorescence. The same hematoxylin/eosin-stained cells showed abnormalities in size and shape. When we treated FRDA fibroblasts with reduced glutathione, we obtained a complete rescue of cytoskeletal abnormalities and cell viability. Thus, we conclude that oxidative stress may induce actin glutathionylation and impairment of cytoskeletal functions in FRDA fibroblasts.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ataxia de Friedreich
/
Actinas
/
Fibroblastos
/
Glutationa
Tipo de estudo:
Etiology_studies
/
Observational_studies
Limite:
Female
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2003
Tipo de documento:
Article