Clearance and Phosphorylation of Alpha-Synuclein Are Inhibited in Methionine Sulfoxide Reductase A Null Yeast Cells
Aggregated α-synuclein and the point mutations Ala30Pro and Ala53Thr of α-synuclein are associated with Parkinson’s disease. The physiological roles of α-synuclein and methionine oxidation of the α-synuclein protein structure and function are not fully understood. Methionine sulfoxide reductase A (MsrA) reduces methionine sulfoxide residues and functions as an antioxidant. To monitor the effect of methionine oxidation to α-synuclein on basic cellular processes, α-synucleins were expressed in msrA null mutant and wild-type yeast cells. Protein degradation was inhibited in the α-synuclein-expressing msrA null mutant cells compared to α-synuclein-expressing wild-type cells. Increased inhibition of degradation and elevated accumulations of fibrillated proteins were observed in SynA30P-expressing msrA null mutant cells. Additionally, methionine oxidation inhibited α-synuclein phosphorylation in yeast cells and in vitro by casein kinase 2. Thus, a compromised MsrA function combined with α-synuclein overexpression may promote processes leading to synucleinopathies.
KeywordsOxidative stress Posttranslation modification Neurodegenerative diseases Parkinson’s disease Antioxidants Protein aggregation Yeast Synuclein
This work was supported by the Kansas EPSCOR/National Science Foundation and the National Institute of Aging, AG027363.
- Midwinter, R. G., Cheah, F. C., Moskovitz, J., Vissers, M. C., & Winterbourn, C. C. (2006). Ikappab is a sensitive target for oxidation by cell-permeable chloramines: Inhibition of NF-kappaB activity by glycine chloramine through methionine oxidation. Biochemical Journal, 396, 71–78.CrossRefPubMedGoogle Scholar
- Moskovitz, J., Bar-Noy, S., Williams, W. M., Requena, J., Berlett, B. S., & Stadtman, E. R. (2001). Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals. Proceedings of the National Academy of Sciences of the United States of America, 98, 12920–12925.CrossRefPubMedGoogle Scholar
- Moskovitz, J., & Stadtman, E. R. (2003). Selenium-deficient diet enhances protein oxidation and affects methionine sulfoxide reductase (MsrB) protein level in certain mouse tissues. Proceedings of the National Academy of Sciences of the United States of America, 100, 7486–7490.CrossRefPubMedGoogle Scholar
- Olry, A., Boschi-Muller, S., Marraud, M., Sanglier-Cianferani, S., Van Dorsselear, A., & Branlant, G. (2002). Characterization of the methionine sulfoxide reductase activities of PILB, a probable virulence factor from Neisseria meningitidis. J Biol Chem, 277, 12016–12022.CrossRefPubMedGoogle Scholar