Methionine oxidation, alpha-synuclein and Parkinson's disease.
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.
Glaser
Charles B
CB
Yamin
Ghiam
G
Uversky
Vladimir N
VN
Fink
Anthony L
AL
D006801:Humans; D008715:Methionine / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D008715:Methionine