Methionine oxidation, α-synuclein and Parkinson's disease

✍ Scribed by Charles B. Glaser; Ghiam Yamin; Vladimir N. Uversky; Anthony L. Fink

• Book ID: 104003369
• Publisher: Elsevier Science
• Year: 2005
• Tongue: English
• Weight: 419 KB
• Volume: 1703
• Category: Article
• ISSN: 1570-9639
• DOI: 10.1016/j.bbapap.2004.10.008

✦ Synopsis

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