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Methionine oxidation, alpha-synuclein and Parkinson's disease.
Biochim Biophys Acta ; 1703(2): 157-69, 2005 Jan 17.
Article em En | MEDLINE | ID: mdl-15680224
The aggregation of normally soluble alpha-synuclein in the dopaminergic neurons of the substantia nigra is a crucial step in the pathogenesis of Parkinson's disease. Oxidative stress is believed to be a contributing factor in this disorder. Because it lacks Trp and Cys residues, mild oxidation of alpha-synuclein in vitro with hydrogen peroxide selectively converts all four methionine residues to the corresponding sulfoxides. Both oxidized and non-oxidized alpha-synucleins have similar unfolded conformations; however, the fibrillation of alpha-synuclein at physiological pH is completely inhibited by methionine oxidation. The inhibition results from stabilization of soluble oligomers of Met-oxidized alpha-synuclein. Furthermore, the Met-oxidized protein also inhibits fibrillation of unmodified alpha-synuclein. The degree of inhibition of fibrillation by Met-oxidized alpha-synuclein is proportional to the number of oxidized methionines. However, the presence of metals can completely overcome the inhibition of fibrillation of the Met-oxidized alpha-synuclein. Since oligomers of aggregated alpha-synuclein may be cytotoxic, these findings indicate that both oxidative stress and environmental metal pollution could play an important role in the aggregation of alpha-synuclein, and hence possibly Parkinson's disease. In addition, if the level of Met-oxidized alpha-synuclein was under the control of methionine sulfoxide reductase (Msr), then this could also be factor in the disease.
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Coleções: 01-internacional Base de dados: MEDLINE Limite: Humans Idioma: En Ano de publicação: 2005 Tipo de documento: Article
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Coleções: 01-internacional Base de dados: MEDLINE Limite: Humans Idioma: En Ano de publicação: 2005 Tipo de documento: Article