Clearance and Phosphorylation of Alpha-Synuclein Are Inhibited in Methionine Sulfoxide Reductase A Null Yeast Cells

  • Derek B. Oien
  • Heather E. Shinogle
  • David S. Moore
  • Jackob Moskovitz
Article

Abstract

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.

Keywords

Oxidative stress Posttranslation modification Neurodegenerative diseases Parkinson’s disease Antioxidants Protein aggregation Yeast Synuclein 

Notes

Acknowledgments

This work was supported by the Kansas EPSCOR/National Science Foundation and the National Institute of Aging, AG027363.

References

  1. Baba, M., Nakajo, S., Tu, P. H., et al. (1998). Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. American Journal of Pathology, 152, 879–884.PubMedGoogle Scholar
  2. Berke, S. J., & Paulson, H. L. (2003). Protein aggregation and the ubiquitin proteasome pathway: gaining the upper hand on neurodegeneration. Current Opinion in Genetics and Development, 13, 253–261.CrossRefPubMedGoogle Scholar
  3. Bigelow, D. J., & Squier, T. C. (2005). Redox modulation of cellular signaling and metabolism through reversible oxidation of methionine sensors in calcium regulatory proteins. Biochimica et Biophysica Acta, 1703, 121–134.PubMedGoogle Scholar
  4. Brandis, K. A., Holmes, I. F., England, S. J., Sharma, N., Kukreja, L., & DebBurman, S. K. (2006). Alpha-synuclein fission yeast model: Concentration-dependent aggregation without plasma membrane localization or toxicity. J Mol Neurosci, 28, 179–191.CrossRefPubMedGoogle Scholar
  5. Bussell, R., Jr., & Eliezer, D. (2003). A structural and functional role for 11-mer repeats in alpha-synuclein and other exchangeable lipid binding proteins. J Mol Biol, 329, 763–778.CrossRefPubMedGoogle Scholar
  6. Chao, C. C., Ma, Y. S., & Stadtman, E. R. (1997). Modification of protein surface hydrophobicity and methionine oxidation by oxidative systems. Proceedings of the National Academy of Sciences of the United States of America, 94, 2969–2974.CrossRefPubMedGoogle Scholar
  7. Chen, L., & Feany, M. B. (2005). Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nature Neuroscience, 8, 657–663.CrossRefPubMedGoogle Scholar
  8. Chen, Q., Thorpe, J., Ding, Q., El-Amouri, I. S., & Keller, J. N. (2004). Proteasome synthesis and assembly are required for survival during stationary phase. Free Radical Biology and Medicine, 37, 859–868.CrossRefPubMedGoogle Scholar
  9. Chen, Q., Thorpe, J., & Keller, J. N. (2005). Alpha-synuclein alters proteasome function, protein synthesis, and stationary phase viability. J Biol Chem, 280, 30009–30017.CrossRefPubMedGoogle Scholar
  10. Fink, A. L. (2006). The aggregation and fibrillation of alpha-synuclein. Acc Chem Res, 39, 628–634.CrossRefPubMedGoogle Scholar
  11. Fujiwara, H., Hasegawa, M., Dohmae, N., et al. (2002). Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nature Cell Biology, 4, 160–164.CrossRefPubMedGoogle Scholar
  12. Giasson, B. I., Duda, J. E., Murray, I. V., et al. (2000). Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science, 290, 985–989.CrossRefPubMedGoogle Scholar
  13. Giorgi, F. S., Bandettini di Poggio, A., Battaglia, G., et al. (2006). A short overview on the role of alpha-synuclein and proteasome in experimental models of Parkinson’s disease. J Neural Transm Suppl, 70, 105–109.CrossRefPubMedGoogle Scholar
  14. Hawe, A., Sutter, M., & Jiskoot, W. (2008). Extrinsic fluorescent dyes as tools for protein characterization. Pharmaceutical Research, 25, 1487–1499.CrossRefPubMedGoogle Scholar
  15. Hsu, L. J., Sagara, Y., Arroyo, A., et al. (2000). Alpha-synuclein promotes mitochondrial deficit and oxidative stress. American Journal of Pathology, 157, 401–410.PubMedGoogle Scholar
  16. Ishii, A., Nonaka, T., Taniguchi, S., et al. (2007). Casein kinase 2 is the major enzyme in brain that phosphorylates ser129 of human alpha-synuclein: Implication for alpha-synucleinopathies. FEBS Letters, 581, 4711–4717.CrossRefPubMedGoogle Scholar
  17. Jo, E., Fuller, N., Rand, R. P., St George-Hyslop, P., & Fraser, P. E. (2002). Defective membrane interactions of familial Parkinson’s disease mutant a30p alpha-synuclein. J Mol Biol, 315, 799–807.CrossRefPubMedGoogle Scholar
  18. Kanayama, A., Inoue, J., Sugita-Konishi, Y., Shimizu, M., & Miyamoto, Y. (2002). Oxidation of Ikappa Balpha at methionine 45 is one cause of taurine chloramine-induced inhibition of NF-kappa B activation. J Biol Chem, 277, 24049–24056.CrossRefPubMedGoogle Scholar
  19. Kruger, R., Kuhn, W., Muller, T., et al. (1998). Ala30pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nature Genetics, 18, 106–108.CrossRefPubMedGoogle Scholar
  20. Lee, H. J., Choi, C., & Lee, S. J. (2002). Membrane-bound alpha-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form. J Biol Chem, 277, 671–678.CrossRefPubMedGoogle Scholar
  21. Lindersson, E., Beedholm, R., Hojrup, P., et al. (2004). Proteasomal inhibition by alpha-synuclein filaments and oligomers. J Biol Chem, 279, 12924–12934.CrossRefPubMedGoogle Scholar
  22. Liu, F., Hindupur, J., Nguyen, J. L., et al. (2008). Methionine sulfoxide reductase a protects dopaminergic cells from parkinson’s disease-related insults. Free Radical Biology and Medicine, 45, 242–255.CrossRefPubMedGoogle Scholar
  23. Lucking, C. B., & Brice, A. (2000). Alpha-synuclein and Parkinson’s disease. Cellular and Molecular Life Sciences, 57, 1894–1908.CrossRefPubMedGoogle Scholar
  24. 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
  25. Mohri, M., Reinach, P. S., Kanayama, A., et al. (2002). Suppression of the TNFalpha-induced increase in IL-1alpha expression by hypochlorite in human corneal epithelial cells. Investigative Ophthalmology and Visual Science, 43, 3190–3195.PubMedGoogle Scholar
  26. Moskovitz, J. (2005). Methionine sulfoxide reductases: Ubiquitous enzymes involved in antioxidant defense, protein regulation, and prevention of aging-associated diseases. Biochimica et Biophysica Acta, 1703, 213–219.PubMedGoogle Scholar
  27. Moskovitz, J. (2007). Prolonged selenium-deficient diet in MsrA knockout mice causes enhanced oxidative modification to proteins and affects the levels of antioxidant enzymes in a tissue-specific manner. Free Radical Research, 41, 162–171.CrossRefPubMedGoogle Scholar
  28. 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
  29. Moskovitz, J., Berlett, B. S., Poston, J. M., & Stadtman, E. R. (1997). The yeast peptide-methionine sulfoxide reductase functions as an antioxidant in vivo. Proceedings of the National Academy of Sciences of the United States of America, 94, 9585–9589.CrossRefPubMedGoogle Scholar
  30. 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
  31. Munishkina, L. A., Henriques, J., Uversky, V. N., & Fink, A. L. (2004). Role of protein–water interactions and electrostatics in alpha-synuclein fibril formation. Biochemistry, 43, 3289–3300.CrossRefPubMedGoogle Scholar
  32. Oien, D., & Moskovitz, J. (2007). Protein-carbonyl accumulation in the non-replicative senescence of the methionine sulfoxide reductase a (MsrA) knockout yeast strain. Amino Acids, 32, 603–606.CrossRefPubMedGoogle Scholar
  33. Oien, D. B., & Moskovitz, J. (2008). Substrates of the methionine sulfoxide reductase system and their physiological relevance. Current Topics in Developmental Biology, 80, 93–133.CrossRefPubMedGoogle Scholar
  34. Oien, D. B., Osterhaus, G. L., Latif, S. A., et al. (2008). Msra knockout mouse exhibits abnormal behavior and brain dopamine levels. Free Radical Biology and Medicine, 45, 193–200.CrossRefPubMedGoogle Scholar
  35. 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
  36. Ostrerova-Golts, N., Petrucelli, L., Hardy, J., Lee, J. M., Farer, M., & Wolozin, B. (2000). The a53t alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci, 20, 6048–6054.PubMedGoogle Scholar
  37. Outeiro, T. F., & Lindquist, S. (2003). Yeast cells provide insight into alpha-synuclein biology and pathobiology. Science, 302, 1772–1775.CrossRefPubMedGoogle Scholar
  38. Pal, R., Oien, D. B., Ersen, F. Y., & Moskovitz, J. (2007). Elevated levels of brain-pathologies associated with neurodegenerative diseases in the methionine sulfoxide reductase a knockout mouse. Experimental Brain Research, 180, 765–774.CrossRefGoogle Scholar
  39. Paleologou, K. E., Schmid, A. W., Rospigliosi, C. C., et al. (2008). Phosphorylation at ser-129 but not the phosphomimics s129e/d inhibits the fibrillation of alpha-synuclein. J Biol Chem, 283, 16895–16905.CrossRefPubMedGoogle Scholar
  40. Polymeropoulos, M. H., Lavedan, C., Leroy, E., et al. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science, 276, 2045–2047.CrossRefPubMedGoogle Scholar
  41. Sawada, H., Kohno, R., Kihara, T., et al. (2004). Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes alpha-synuclein inclusions. J Biol Chem, 279, 10710–10719.CrossRefPubMedGoogle Scholar
  42. Sharma, N., Brandis, K. A., Herrera, S. K., et al. (2006). Alpha-synuclein budding yeast model: Toxicity enhanced by impaired proteasome and oxidative stress. J Mol Neurosci, 28, 161–178.CrossRefPubMedGoogle Scholar
  43. Singleton, A. B., Farrer, M., Johnson, J., et al. (2003). Alpha-synuclein locus triplication causes Parkinson’s disease. Science, 302, 841.CrossRefPubMedGoogle Scholar
  44. Smith, W. W., Margolis, R. L., Li, X., et al. (2005). Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in sh-sy5y cells. J Neurosci, 25, 5544–5552.CrossRefPubMedGoogle Scholar
  45. Snyder, H., Mensah, K., Hsu, C., et al. (2005). Beta-synuclein reduces proteasomal inhibition by alpha-synuclein but not gamma-synuclein. J Biol Chem, 280, 7562–7569.CrossRefPubMedGoogle Scholar
  46. Stadtman, E. R., & Berlett, B. S. (1998). Reactive oxygen-mediated protein oxidation in aging and disease. Drug Metabolism Reviews, 30, 225–243.CrossRefPubMedGoogle Scholar
  47. Starke-Reed, P. E., & Oliver, C. N. (1989). Protein oxidation and proteolysis during aging and oxidative stress. Archives of Biochemistry and Biophysics, 275, 559–567.CrossRefPubMedGoogle Scholar
  48. Takeda, A., Mallory, M., Sundsmo, M., Honer, W., Hansen, L., & Masliah, E. (1998). Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. American Journal of Pathology, 152, 367–372.PubMedGoogle Scholar
  49. Vekrellis, K., Rideout, H. J., & Stefanis, L. (2004). Neurobiology of alpha-synuclein. Molecular Neurobiology, 30, 1–21.CrossRefPubMedGoogle Scholar
  50. Willingham, S., Outeiro, T. F., DeVit, M. J., Lindquist, S. L., & Muchowski, P. J. (2003). Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein. Science, 302, 1769–1772.CrossRefPubMedGoogle Scholar
  51. Yamin, G., Glaser, C. B., Uversky, V. N., & Fink, A. L. (2003). Certain metals trigger fibrillation of methionine-oxidized alpha-synuclein. J Biol Chem., 278, 27630–27635.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press 2009

Authors and Affiliations

  • Derek B. Oien
    • 1
  • Heather E. Shinogle
    • 2
  • David S. Moore
    • 2
  • Jackob Moskovitz
    • 1
  1. 1.Department of Pharmacology and Toxicology, School of PharmacyUniversity of KansasLawrenceUSA
  2. 2.Department of Biomedical Services LabsUniversity of KansasLawrenceUSA

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