Table of Contents Author Guidelines Submit a Manuscript
Parkinson’s Disease
Volume 2011 (2011), Article ID 392180, 12 pages
http://dx.doi.org/10.4061/2011/392180
Research Article

Contribution of Alanine-76 and Serine Phosphorylation in α-Synuclein Membrane Association and Aggregation in Yeasts

Biology Department, Lake Forest College, Box P7, 555 North Sheridan Road, Lake Forest, IL 60045, USA

Received 14 February 2011; Accepted 1 April 2011

Academic Editor: T. M. Dawson

Copyright © 2011 Michael Fiske et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. M. G. Spillantini, R. A. Crowther, R. Jakes, M. Hasegawa, and M. Goedert, “α-synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 11, pp. 6469–6473, 1998. View at Publisher · View at Google Scholar · View at Scopus
  2. K. Wakabayashi, Y. Toyoshima, K. Awamori et al., “Restricted occurrence of Lewy bodies in the dorsal vagal nucleus in a patient with late-onset parkinsonism,” Journal of the Neurological Sciences, vol. 165, no. 2, pp. 188–191, 1999. View at Publisher · View at Google Scholar · View at Scopus
  3. D. J. Burn and E. Jaros, “Multiple system atrophy: cellular and molecular pathology,” Journal of Clinical Pathology, vol. 54, no. 6, pp. 419–426, 2001. View at Google Scholar · View at Scopus
  4. J. L. Heidebrink, “Is dementia with Lewy bodies the second most common cause of dementia?” Journal of Geriatric Psychiatry and Neurology, vol. 15, no. 4, pp. 182–187, 2002. View at Google Scholar · View at Scopus
  5. M. Goedert, “Alpha-synuclein and neurodegenerative diseases,” Nature Reviews Neuroscience, vol. 2, no. 7, pp. 492–501, 2001. View at Publisher · View at Google Scholar · View at Scopus
  6. E. R. Dorsey, R. Constantinescu, J. P. Thompson et al., “Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030,” Neurology, vol. 68, no. 5, pp. 384–386, 2007. View at Publisher · View at Google Scholar · View at Scopus
  7. M. H. Polymeropoulos, C. Lavedan, E. Leroy et al., “Mutation in the α-synuclein gene identified in families with Parkinson's disease,” Science, vol. 276, no. 5321, pp. 2045–2047, 1997. View at Publisher · View at Google Scholar · View at Scopus
  8. R. Krüger, W. Kuhn, K. L. Leenders et al., “Familial parkinsonism with synuclein pathology: clinical and PET studies of A30P mutation carriers,” Neurology, vol. 56, no. 10, pp. 1355–1362, 2001. View at Google Scholar · View at Scopus
  9. J. J. Zarranz, J. Alegre, J. C. Gómez-Esteban et al., “The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia,” Annals of Neurology, vol. 55, no. 2, pp. 164–173, 2004. View at Publisher · View at Google Scholar
  10. A. B. Singleton, M. Farrer, J. Johnson et al., “α-synuclein locus triplication causes Parkinson's disease,” Science, vol. 302, no. 5646, p. 841, 2003. View at Publisher · View at Google Scholar
  11. M. C. Chartier-Harlin, J. Kachergus, C. Roumier et al., “α-synuclein locus duplication as a cause of familial Parkinson's disease,” The Lancet, vol. 364, no. 9440, pp. 1167–1169, 2004. View at Publisher · View at Google Scholar · View at Scopus
  12. D. M. Maraganore, M. de Andrade, A. Elbaz et al., “Collaborative analysis of α-synuclein gene promoter variability and Parkinson disease,” Journal of the American Medical Association, vol. 296, no. 6, pp. 661–670, 2006. View at Publisher · View at Google Scholar
  13. K. Ueda, H. Fukushima, E. Masliah et al., “Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 23, pp. 11282–11286, 1993. View at Publisher · View at Google Scholar · View at Scopus
  14. J. M. George, “The synucleins,” Genome Biology, vol. 3, no. 1, article 3002, 2002. View at Google Scholar · View at Scopus
  15. D. D. Murphy, S. M. Rueter, J. Q. Trojanowski, and V. M. Y. Lee, “Synucleins are developmentally expressed, and α-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons,” Journal of Neuroscience, vol. 20, no. 9, pp. 3214–3220, 2000. View at Google Scholar · View at Scopus
  16. K. A. Jellinger, “Formation and development of Lewy pathology: a critical update,” Journal of Neurology, vol. 256, no. 3, pp. S270–S279, 2009. View at Publisher · View at Google Scholar · View at Scopus
  17. K. Beyer, “Mechanistic aspects of Parkinson's disease: α-synuclein and the biomembrane,” Cell Biochemistry and Biophysics, vol. 47, no. 2, pp. 285–299, 2007. View at Publisher · View at Google Scholar · View at Scopus
  18. H. Shimura, M. G. Schlossmacher, N. Hattori et al., “Ubiquitination of a new form of α-synuclein by parkin from human brain: implications for Parkinson's disease,” Science, vol. 293, no. 5528, pp. 263–269, 2001. View at Publisher · View at Google Scholar
  19. B. I. Giasson, I. V. J. Murray, J. Q. Trojanowski, and V. M. Y. Lee, “A hydrophobic stretch of 12 amino acid residues in the middle of α-synuclein is essential for filament assembly,” Journal of Biological Chemistry, vol. 276, no. 4, pp. 2380–2386, 2001. View at Publisher · View at Google Scholar · View at Scopus
  20. R. Hodara, E. H. Norris, B. I. Giasson et al., “Functional consequences of α-synuclein tyrosine nitration: diminished binding to lipid vesicles and increased fibril formation,” Journal of Biological Chemistry, vol. 279, no. 46, pp. 47746–47753, 2004. View at Publisher · View at Google Scholar · View at Scopus
  21. M. Okochi, J. Walter, A. Koyama et al., “Constitutive phosphorylation of the Parkinson's disease associated α-synuclein,” Journal of Biological Chemistry, vol. 275, no. 1, pp. 390–397, 2000. View at Publisher · View at Google Scholar · View at Scopus
  22. H. Fujiwara, M. Hasegawa, N. Dohmae et al., “α-synuclein is phosphorylated in synucleinopathy lesions,” Nature Cell Biology, vol. 4, no. 2, pp. 160–164, 2002. View at Publisher · View at Google Scholar · View at Scopus
  23. F. Chiti, M. Stefani, N. Taddel, G. Ramponi, and C. M. Dobson, “Rationalization of the effects of mutations on peptide and protein aggregation rates,” Nature, vol. 424, no. 6950, pp. 805–808, 2003. View at Publisher · View at Google Scholar · View at Scopus
  24. H. J. Koo, H. J. Lee, and H. Im, “Sequence determinants regulating fibrillation of human α-synuclein,” Biochemical and Biophysical Research Communications, vol. 368, no. 3, pp. 772–778, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. K. E. Paleologou, A. Oueslati, G. Shakked et al., “Phosphorylation at S87 is enhanced in synucleinopathies, inhibits α-synuclein oligomerization, and influences synuclein-membrane interactions,” Journal of Neuroscience, vol. 30, no. 9, pp. 3184–3198, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. W. W. Smith, R. L. Margolis, X. Li et al., “α-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells,” Journal of Neuroscience, vol. 25, no. 23, pp. 5544–5552, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. L. Chen and M. B. Feany, “α-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease,” Nature Neuroscience, vol. 8, no. 5, pp. 657–663, 2005. View at Publisher · View at Google Scholar · View at Scopus
  28. O. S. Gorbatyuk, S. Li, L. F. Sullivan et al., “The phosphorylation state of Ser-129 in human α-synuclein determines neurodegeneration in a rat model of Parkinson disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 2, pp. 763–768, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. S. A. da Silveira, B. L. Schneider, C. Cifuentes-Diaz et al., “Phosphorylation does not prompt, nor prevent, the formation of α-synuclein toxic species in a rat model of Parkinson's disease,” Human Molecular Genetics, vol. 18, no. 5, pp. 872–887, 2009. View at Publisher · View at Google Scholar · View at Scopus
  30. N. R. McFarland, Z. Fan, K. Xu et al., “α-synuclein S129 phosphorylation mutants do not alter nigrostriatal toxicity in a rat model of parkinson disease,” Journal of Neuropathology and Experimental Neurology, vol. 68, no. 5, pp. 515–524, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. V. N. Uversky and A. L. Fink, “Amino acid determinants of α-synuclein aggregation: putting together pieces of the puzzle,” FEBS Letters, vol. 522, no. 1-3, pp. 9–13, 2002. View at Publisher · View at Google Scholar · View at Scopus
  32. A. M. Bodles, D. J. S. Guthrie, B. Greer, and G. Brent Irvine, “Identification of the region of non-Aβ component (NAC) of Alzheimer's disease amyloid responsible for its aggregation and toxicity,” Journal of Neurochemistry, vol. 78, no. 2, pp. 384–395, 2001. View at Publisher · View at Google Scholar · View at Scopus
  33. W. Li, N. West, E. Colla et al., “Aggregation promoting C-terminal truncation of α-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 6, pp. 2162–2167, 2005. View at Publisher · View at Google Scholar · View at Scopus
  34. P. H. Weinreb, W. Zhen, A. W. Poon, K. A. Conway, and P. T. Lansbury Jr., “NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded,” Biochemistry, vol. 35, no. 43, pp. 13709–13715, 1996. View at Publisher · View at Google Scholar · View at Scopus
  35. H. Han, P. H. Weinreb, and P. T. Lansbury Jr., “The core Alzheimer's peptide NAC forms amyloid fibrils which seed and are seeded by beta-amyloid: is NAC a common trigger or target in neurodegenerative disease?” Chemistry and Biology, vol. 2, no. 3, pp. 163–169, 1995. View at Google Scholar · View at Scopus
  36. A. Iwai, M. Yoshimoto, E. Masliah, and T. Saitoh, “Non-Aβ component of Alzheimer's disease amyloid (NAC) is amyloidogenic,” Biochemistry, vol. 34, no. 32, pp. 10139–10145, 1995. View at Google Scholar · View at Scopus
  37. E. A. Waxman, J. R. Mazzulli, and B. I. Giasson, “Characterization of hydrophobic residue requirements for α-synuclein fibrillization,” Biochemistry, vol. 48, no. 40, pp. 9427–9436, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. T. F. Outeiro and S. Lindquist, “Yeast cells provide insight into alpha-synuclein biology and pathobiology,” Science, vol. 302, no. 5651, pp. 1772–1775, 2003. View at Publisher · View at Google Scholar · View at Scopus
  39. S. Willingham, T. F. Outeiro, M. J. DeVit, S. L. Lindquist, and P. J. Muchowski, “Yeast genes that enhance the toxicity of a mutant huntingtin fragment or α-synuclein,” Science, vol. 302, no. 5651, pp. 1769–1772, 2003. View at Publisher · View at Google Scholar · View at Scopus
  40. P. Zabrocki, K. Pellens, T. Vanhelmont et al., “Characterization of α-synuclein aggregation and synergistic toxicity with protein tau in yeast,” FEBS Journal, vol. 272, no. 6, pp. 1386–1400, 2005. View at Publisher · View at Google Scholar · View at Scopus
  41. N. Sharma, K. A. Brandis, S. K. Herrera et al., “α-synuclein budding yeast model: toxicity enhanced by impaired proteasome and oxidative stress,” Journal of Molecular Neuroscience, vol. 28, no. 2, pp. 161–178, 2006. View at Publisher · View at Google Scholar · View at Scopus
  42. C. Dixon, N. Mathias, R. M. Zweig, D. A. Davis, and D. S. Gross, “α-synuclein targets the plasma membrane via the secretory pathway and induces toxicity in yeast,” Genetics, vol. 170, no. 1, pp. 47–59, 2005. View at Publisher · View at Google Scholar · View at Scopus
  43. J. H. Soper, S. Roy, A. Stieber et al., “α-synuclein-induced aggregation of cytoplasmic vesicles in Saccharomyces cerevisiae,” Molecular Biology of the Cell, vol. 19, no. 3, pp. 1093–1103, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. K. Vamvaca, M. J. Volles, and P. T. Lansbury Jr., “The first N-terminal amino acids of α-synuclein are essential for α-helical structure formation in vitro and membrane binding in yeast,” Journal of Molecular Biology, vol. 389, no. 2, pp. 413–424, 2009. View at Publisher · View at Google Scholar · View at Scopus
  45. K. A. Brandis, I. F. Holmes, S. J. England, N. Sharma, L. Kukreja, and S. K. DebBurman, “α-synuclein fission yeast model: concentration-dependent aggregation without plasma membrane localization or toxicity,” Journal of Molecular Neuroscience, vol. 28, no. 2, pp. 179–192, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. E. Yeger-Lotem, L. Riva, L. J. Su et al., “Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity,” Nature Genetics, vol. 41, no. 3, pp. 316–323, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. M. Takahashi, H. Kanuka, H. Fujiwara et al., “Phosphorylation of α-synuclein characteristic of synucleinopathy lesions is recapitulated in α-synuclein transgenic Drosophila,” Neuroscience Letters, vol. 336, no. 3, pp. 155–158, 2003. View at Publisher · View at Google Scholar · View at Scopus
  48. M. Yamada, T. Iwatsubo, Y. Mizuno, and H. Mochizuki, “Overexpression of α-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of α-synuclein and activation of caspase-9: resemblance to pathogenetic changes in Parkinson's disease,” Journal of Neurochemistry, vol. 91, no. 2, pp. 451–461, 2004. View at Publisher · View at Google Scholar · View at Scopus
  49. E. A. Waxman and B. I. Giasson, “Specificity and regulation of casein kinase-mediated phosphorylation of α-synuclein,” Journal of Neuropathology and Experimental Neurology, vol. 67, no. 5, pp. 402–416, 2008. View at Publisher · View at Google Scholar · View at Scopus
  50. A. N. Pronin, A. J. Morris, A. Surguchov, and J. L. Benovic, “Synucleins are a novel class of substrates for G protein-coupled receptor kinases,” Journal of Biological Chemistry, vol. 275, no. 34, pp. 26515–26522, 2000. View at Publisher · View at Google Scholar · View at Scopus
  51. H. Qing, W. Wong, E. G. McGeer, and P. L. McGeer, “Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications,” Biochemical and Biophysical Research Communications, vol. 387, no. 1, pp. 149–152, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. K. J. Inglis, D. Chereau, E. F. Brigham et al., “Polo-like kinase 2 (PLK2) phosphorylates α-synuclein at serine 129 in central nervous system,” Journal of Biological Chemistry, vol. 284, no. 5, pp. 2598–2602, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. M. K. Mbefo, K. E. Paleologou, A. Boucharaba et al., “Phosphorylation of synucleins by members of the polo-like kinase family,” Journal of Biological Chemistry, vol. 285, no. 4, pp. 2807–2822, 2010. View at Publisher · View at Google Scholar · View at Scopus
  54. M. Periquet, T. Fulga, L. Myllykangas, M. G. Schlossmacher, and M. B. Feany, “Aggregated α-synuclein mediates dopaminergic neurotoxicity in vivo,” Journal of Neuroscience, vol. 27, no. 12, pp. 3338–3346, 2007. View at Publisher · View at Google Scholar · View at Scopus
  55. L. Chen, M. Periquet, XU. Wang et al., “Tyrosine and serine phosphorylation of α-synuclein have opposing effects on neurotoxicity and soluble oligomer formation,” Journal of Clinical Investigation, vol. 119, no. 11, pp. 3257–3265, 2009. View at Publisher · View at Google Scholar · View at Scopus
  56. P. T. Lansbury Jr., “Evolution of amyloid: what normal protein folding may tell us about fibrillogenesis and disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 7, pp. 3342–3344, 1999. View at Publisher · View at Google Scholar · View at Scopus
  57. M. S. Goldberg and P. T. Lansbury Jr., “Is there a cause-and-effect relationship between α-synuclein fibrillization and Parkinson's disease?” Nature Cell Biology, vol. 2, no. 7, pp. E115–E119, 2000. View at Publisher · View at Google Scholar
  58. N. Gosavi, H. J. Lee, J. S. Lee, S. Patel, and S. J. Lee, “Golgi fragmentation occurs in the cells with prefibrillar α-synuclein aggregates and precedes the formation of fibrillar inclusion,” Journal of Biological Chemistry, vol. 277, no. 50, pp. 48984–48992, 2002. View at Publisher · View at Google Scholar · View at Scopus
  59. P. K. Auluck, G. Caraveo, and S. Lindquist, “α-synuclein: membrane interactions and toxicity in parkinson's disease,” Annual Review of Cell and Developmental Biology, vol. 26, pp. 211–233, 2010. View at Publisher · View at Google Scholar
  60. T. R. Flower, C. Clark-Dixon, C. Metoyer et al., “YGR198w (YPP1) targets A30P α-synuclein to the vacuole for degradation,” Journal of Cell Biology, vol. 177, no. 6, pp. 1091–1104, 2007. View at Publisher · View at Google Scholar · View at Scopus