Methionine oxidation, α-synuclein and Parkinson's disease

Abstract

The aggregation of normally soluble α-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 α-synuclein in vitro with hydrogen peroxide selectively converts all four methionine residues to the corresponding sulfoxides. Both oxidized and non-oxidized α-synucleins have similar unfolded conformations; however, the fibrillation of α-synuclein at physiological pH is completely inhibited by methionine oxidation. The inhibition results from stabilization of soluble oligomers of Met-oxidized α-synuclein. Furthermore, the Met-oxidized protein also inhibits fibrillation of unmodified α-synuclein. The degree of inhibition of fibrillation by Met-oxidized α-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 α-synuclein. Since oligomers of aggregated α-synuclein may be cytotoxic, these findings indicate that both oxidative stress and environmental metal pollution could play an important role in the aggregation of α-synuclein, and hence possibly Parkinson's disease. In addition, if the level of Met-oxidized α-synuclein was under the control of methionine sulfoxide reductase (Msr), then this could also be factor in the disease.