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Cell Biology of α-Synuclein: Implications in Parkinson’s Disease and Other Lewy Body Diseases

  • Seung-Jae Lee
  • Yoon Suk Kim
Part of the Protein Reviews book series (PRON, volume 6)

Abstract

Missense mutations and gene multiplication in the α-synuclein gene cause inherited forms of Parkinson’s disease (PD), and deposition of amyloid fibrils composed of wild-type α-synuclein in Lewy bodies and Lewy neurites is a pathologic hallmark of sporadic PD and other related neurodegenerative diseases such as dementia with Lewy bodies. These findings, along with the studies in animal models, strongly suggest that misfolding and aggregation of α-synuclein is a critical component in the pathogenesis of these disorders. Though the physiologic function of α-synuclein has not been completely defined, there has been a body of evidence supporting its roles in synaptic transmission, synaptic vesicle biogenesis, and lipid transport and metabolism. More importantly, based on the lack of neurodegenerative phenotypes in synuclein knockout animals, it has been suggested that loss of normal function of this protein might not be the direct cause of PD. α-Synuclein forms various types of nonfibrillar and fibrillar aggregates. PD-linked mutations accelerate the aggregation process in one or more steps in the fibrillation. Although some oligomeric aggregates seem to be toxic to cell, leading to functional abnormalities such as proteasomal and lysosomal dysfunctions, mitochondrial deficits, and Golgi fragmentation and transport defects, cells have defense mechanisms against these potentially toxic oligomeric aggregates. The free oligomers are transported to and deposited in the pericentriolar region by the microtubule system, resulting in the sequestration of toxic aggregates. After deposition, the transition from oligomers to fibrils occurs, forming Lewy body-like inclusion bodies and perhaps transforming toxic species into inert aggregates. Moreover, we have also shown that cells can degrade the preformed oligomers by autophagy. Elucidation of the mechanisms of the cellular aggregation process and the handling of preformed toxic aggregates should greatly enhance our understanding of the disease and provide rational targets for therapeutic intervention.

Keywords

Inclusion Body Lewy Body Amyloid Fibril Inclusion Body Formation Autophagic Degradation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Abeliovich, A., Schmitz, Y., Farinas, I., Choi-Lundberg, D., Ho, W. H., Castillo, P. E., Shinsky, N., Verdugo, J. M., Armanini, M., Ryan, A., Hynes, M., Phillips, H., Sulzer, D. and Rosenthal, A. (2000). Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25: 239–252.PubMedCrossRefGoogle Scholar
  2. Albani, D., Peverelli, E., Rametta, R., Batelli, S., Veschini, L., Negro, A. and Forloni, G. (2004). Protective effect of TAT-delivered alpha-synuclein: relevance of the C-terminal domain and involvement of HSP70. FASEB J 18: 1713–1715.PubMedGoogle Scholar
  3. Alim, M. A., Hossain, M. S., Arima, K., Takeda, K., Izumiyama, Y., Nakamura, M., Kaji, H., Shinoda, T., Hisanaga, S. and Ueda, K. (2002). Tubulin seeds alpha-synuclein fibril formation. J Biol Chem 277: 2112–2117.PubMedCrossRefGoogle Scholar
  4. Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R. and Finkbeiner, S. (2004). Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431: 805–810.PubMedCrossRefGoogle Scholar
  5. Baba, M., Nakajo, S., Tu, P. H., Tomita, T., Nakaya, K., Lee, V. M., Trojanowski, J. Q. and Iwatsubo, T. (1998). Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152: 879–884.PubMedGoogle Scholar
  6. Bennett, M. C., Bishop, J. F., Leng, Y., Chock, P. B., Chase, T. N. and Mouradian, M. M. (1999). Degradation of alpha-synuclein by proteasome. J Biol Chem 274: 33855–33858.PubMedCrossRefGoogle Scholar
  7. Betarbet, R., Sherer, T. B., MacKenzie, G., Garcia-Osuna, M., Panov, A. V. and Greenamyre, J. T. (2000). Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3: 1301–1306PubMedCrossRefGoogle Scholar
  8. Bonifati, V., Oostra, B. A. and Heutink, P. (2004). Unraveling the pathogenesis of Parkinson’s disease—the contribution of monogenic forms. Cell Mol Life Sci 61: 1729–1750.PubMedCrossRefGoogle Scholar
  9. Bussell, R., Jr. and 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.PubMedCrossRefGoogle Scholar
  10. Cabin, D. E., Shimazu, K., Murphy, D., Cole, N. B., Gottschalk, W., McIlwain, K. L., Orrison, B., Chen, A., Ellis, C. E., Paylor, R., Lu, B. and Nussbaum, R. L. (2002). Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 22: 8797–8807.PubMedGoogle Scholar
  11. Campbell, B. C., McLean, C. A., Culvenor, J. G., Gai, W. P., Blumbergs, P. C., Jakala, P., Beyreuther, K., Masters, C. L. and Li, Q. X. (2001). The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson’s disease. J Neurochem 76: 87–96.PubMedCrossRefGoogle Scholar
  12. Chandra, S., Chen, X., Rizo, J., Jahn, R. and Sudhof, T. C. (2003). A broken alpha-helix in folded alpha-Synuclein. J Biol Chem 278: 15313–15318.PubMedCrossRefGoogle Scholar
  13. Chandra, S., Fornai, F., Kwon, H. B., Yazdani, U., Atasoy, D., Liu, X., Hammer, R. E., Battaglia, G., German, D. C., Castillo, P. E. and Sudhof, T. C. (2004). Double-knockout mice for alpha-and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci USA 101: 14966–14971.PubMedCrossRefGoogle Scholar
  14. Choi, W., Zibaee, S., Jakes, R., Serpell, L. C., Davletov, B., Crowther, R. A. and Goedert, M. (2004). Mutation E46K increases phospholipid binding and assembly into filaments of human alpha-synuclein. FEBS Lett 576: 363–368.PubMedCrossRefGoogle Scholar
  15. Clayton, D. F. and George, J. M. (1998). The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci 21: 249–254.PubMedCrossRefGoogle Scholar
  16. Cole, N. B., Murphy, D. D., Grider, T., Rueter, S., Brasaemle, D. and Nussbaum, R. L. (2002). Lipid droplet binding and oligomerization properties of the Parkinson’s disease protein alpha-synuclein. J Biol Chem 277: 6344–6352.PubMedCrossRefGoogle Scholar
  17. Conway, K. A., Harper, J. D. and Lansbury, P. T., Jr. (2000a). Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson’s disease are typical amyloid. Biochemistry 39: 2552–2563.PubMedCrossRefGoogle Scholar
  18. Conway, K. A., Lee, S.-J., Rochet, J. C., Ding, T. T., Williamson, R. E. and Lansbury, P. T., Jr. (2000b). Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. Proc Natl Acad Sci USA 97: 571–576.PubMedCrossRefGoogle Scholar
  19. Crowther, R. A., Jakes, R., Spillantini, M. G. and Goedert, M. (1998). Synthetic filaments assembled from C-terminally truncated alpha-synuclein. FEBS Lett 436: 309–312.PubMedCrossRefGoogle Scholar
  20. Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T. and Sulzer, D. (2004). Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305: 1292–1295.PubMedCrossRefGoogle Scholar
  21. Cummings, C. J., Reinstein, E., Sun, Y., Antalffy, B., Jiang, Y., Ciechanover, A., Orr, H. T., Beaudet, A. L. and Zoghbi, H. Y. (1999). Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24: 879–892.PubMedCrossRefGoogle Scholar
  22. da Costa, C. A., Ancolio, K. and Checler, F. (2000). Wild-type but not Parkinson’s disease-related ala-53 → Thr mutant alpha-synuclein protects neuronal cells from apoptotic stimuli. J Biol Chem 275: 24065–24069.PubMedCrossRefGoogle Scholar
  23. Dauer, W. and Przedborski, S. (2003). Parkinson’s disease: mechanisms and models. Neuron 39: 889–909.PubMedCrossRefGoogle Scholar
  24. Davidson, W. S., Jonas, A., Clayton, D. F. and George, J. M. (1998). Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem 273: 9443–9449.PubMedCrossRefGoogle Scholar
  25. Engelender, S., Kaminsky, Z., Guo, X., Sharp, A. H., Amaravi, R. K., Kleiderlein, J. J., Margolis, R. L., Troncoso, J. C., Lanahan, A. A., Worley, P. F., Dawson, V. L., Dawson, T. M. and Ross, C. A. (1999). Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nat Genet 22: 110–114.PubMedCrossRefGoogle Scholar
  26. Faber, P. W., Alter, J. R., MacDonald, M. E. and Hart, A. C. (1999). Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc Natl Acad Sci USA 96: 179–184.PubMedCrossRefGoogle Scholar
  27. Feany, M. B. and Bender, W. W. (2000). A Drosophila model of Parkinson’s disease. Nature 404: 394–398.PubMedCrossRefGoogle Scholar
  28. Fujiwara, H., Hasegawa, M., Dohmae, N., Kawashima, A., Masliah, E., Goldberg, M. S., Shen, J., Takio, K. and Iwatsubo, T. (2002). alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4: 160–164.PubMedCrossRefGoogle Scholar
  29. George, J. M. (2002). The synucleins. Genome Biol 3: reviews 3002.1–3002.6.Google Scholar
  30. George, J. M., Jin, H., Woods, W. S. and Clayton, D. F. (1995). Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15: 361–372.PubMedCrossRefGoogle Scholar
  31. Ghee, M., Fournier, A. and Mallet, J. (2000). Rat alpha-synuclein interacts with Tat binding protein 1, a component of the 26S proteasomal complex. J Neurochem 75: 2221–2224.PubMedCrossRefGoogle Scholar
  32. Giasson, B. I., Duda, J. E., Quinn, S. M., Zhang, B., Trojanowski, J. Q. and Lee, V. M.-Y. (2002). Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34: 521–533.PubMedCrossRefGoogle Scholar
  33. Goedert, M. (2001). Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2: 492–501.PubMedCrossRefGoogle Scholar
  34. Gomez-Santos, C., Ferrer, I., Reiriz, J., Vinals, F., Barrachina, M. and Ambrosio, S. (2002). MPP+ increases alpha-synuclein expression and ERK/MAP-kinase phosphorylation in human neuroblastoma SH-SY5Y cells. Brain Res 935: 32–39.PubMedCrossRefGoogle Scholar
  35. Gosavi, N., Lee, H.-J., Lee, J. S., Patel, S. and Lee, S.-J. (2002). Golgi fragmentation occurs in the cells with prefibrillar alpha-synuclein aggregates and precedes the formation of fibrillar inclusion. J Biol Chem 277: 48984–48992.PubMedCrossRefGoogle Scholar
  36. Hashimoto, M., Hsu, L. J., Rockenstein, E., Takenouchi, T., Mallory, M. and Masliah, E. (2002). alpha-Synuclein protects against oxidative stress via inactivation of the C-jun N-terminal kinase stress signaling pathway in neuronal cells. J Biol Chem 14: 14.Google Scholar
  37. Horwich, A. (2002). Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions. J Clin Invest 110: 1221–1232.PubMedCrossRefGoogle Scholar
  38. Hoyer, W., Cherny, D., Subramaniam, V. and Jovin, T. M. (2004). Rapid self-assembly of alpha-synuclein observed by in situ atomic force microscopy. J Mol Biol 340: 127–139.PubMedCrossRefGoogle Scholar
  39. Hsu, L. J., Mallory, M., Xia, Y., Veinbergs, I., Hashimoto, M., Yoshimoto, M., Thal, L. J., Saitoh, T. and Masliah, E. (1998). Expression pattern of synucleins (non-Abeta component of Alzheimer’s disease amyloid precursor protein/alpha-synuclein) during murine brain development. J Neurochem 71: 338–344.PubMedGoogle Scholar
  40. Hsu, L. J., Sagara, Y., Arroyo, A., Rockenstein, E., Sisk, A., Mallory, M., Wong, J., Takenouchi, T., Hashimoto, M. and Masliah, E. (2000). alpha-Synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol 157: 401–410.PubMedGoogle Scholar
  41. Hyun, D. H., Lee, M., Halliwell, B. and Jenner, P. (2003). Proteasomal inhibition causes the formation of protein aggregates containing a wide range of proteins, including nitrated proteins. J Neurochem 86: 363–373.PubMedCrossRefGoogle Scholar
  42. Irizarry, M. C., Kim, T. W., McNamara, M., Tanzi, R. E., George, J. M., Clayton, D. F. and Hyman, B. T. (1996). Characterization of the precursor protein of the non-A beta component of senile plaques (NACP) in the human central nervous system. J Neuropathol Exp Neurol 55: 889–895.PubMedGoogle Scholar
  43. Iwai, A., Masliah, E., Yoshimoto, M., Ge, N., Flanagan, L., de Silva, H. A., Kittel, A. and Saitoh, T. (1995). The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14: 467–475.PubMedCrossRefGoogle Scholar
  44. Iwata, A., Maruyama, M., Kanazawa, I. and Nukina, N. (2001). alpha-Synuclein affects the MAPK pathway and accelerates cell death. J Biol Chem 276: 45320–45329.PubMedCrossRefGoogle Scholar
  45. Iwata, A., Maruyama, M., Akagi, T., Hashikawa, T., Kanazawa, I., Tsuji, S. and Nukina, N. (2003). Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies. Hum Mol Genet 12: 2625–2635.PubMedCrossRefGoogle Scholar
  46. Jakes, R., Spillantini, M. G. and Goedert, M. (1994). Identification of two distinct synucleins from human brain. FEBS Lett 345: 27–32.PubMedCrossRefGoogle Scholar
  47. Jao, C. C., Der-Sarkissian, A., Chen, J. and Langen, R. (2004). Structure of membrane-bound alpha-synuclein studied by sitedirected spin labeling. Proc Natl Acad Sci USA 101: 8331–8336.PubMedCrossRefGoogle Scholar
  48. Jenco, J. M., Rawlingson, A., Daniels, B. and Morris, A. J. (1998). Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by alpha-and beta-synucleins. Biochemistry 37: 4901–4909.PubMedCrossRefGoogle Scholar
  49. Junn, E. and Mouradian, M. M. (2002). Human alpha-synuclein overexpression increases intracellular reactive oxygen species levels and susceptibility to dopamine. Neurosci Lett 320: 146–150.PubMedCrossRefGoogle Scholar
  50. Kalivendi, S. V., Cunningham, S., Kotamraju, S., Joseph, J., Hillard, C. J. and Kalyanaraman, B. (2004). Alpha-synuclein up-regulation and aggregation during MPP+-induced apoptosis in neuroblastoma cells: intermediacy of transferrin receptor iron and hydrogen peroxide. J Biol Chem 279: 15240–15247.PubMedCrossRefGoogle Scholar
  51. Kanda, S., Bishop, J. F., Eglitis, M. A., Yang, Y. and Mouradian, M. M. (2000). Enhanced vulnerability to oxidative stress by alpha-synuclein mutations and C-terminal truncation. Neuroscience 97: 279–284.PubMedCrossRefGoogle Scholar
  52. Kazemi-Esfarjani, P. and Benzer, S. (2000). Genetic suppression of polyglutamine toxicity in Drosophila. Science 287: 1837–1840.PubMedCrossRefGoogle Scholar
  53. Kim, S. J., Sung, J. Y., Um, J. W., Hattori, N., Mizuno, Y., Tanaka, K., Paik, S. R., Kim, J. and Chung, K. C. (2003). Parkin cleaves intracellular alpha-synuclein inclusions via the activation of calpain. J Biol Chem 278: 41890–41899.PubMedCrossRefGoogle Scholar
  54. Kim, T. D., Paik, S. R. and Yang, C. H. (2002). Structural and functional implications of C-terminal regions of alpha-synuclein. Biochemistry 41: 13782–13790.PubMedCrossRefGoogle Scholar
  55. Kim, T. D., Paik, S. R., Yang, C. H. and Kim, J. (2000). Structural changes in alpha-synuclein affect its chaperone-like activity in vitro. Protein Sci 9: 2489–2496.PubMedCrossRefGoogle Scholar
  56. Kim, T. D., Choi, E., Rhim, H., Paik, S. R. and Yang, C. H. (2004). Alpha-synuclein has structural and functional similarities to small heat shock proteins. Biochem Biophys Res Commun 324: 1352–1359.PubMedCrossRefGoogle Scholar
  57. Klement, I. A., Skinner, P. J., Kaytor, M. D., Yi, H., Hersch, S. M., Clark, H. B., Zoghbi, H. Y. and Orr, H. T. (1998). Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice [see comments]. Cell 95: 41–53.PubMedCrossRefGoogle Scholar
  58. Ko, L., Mehta, N. D., Farrer, M., Easson, C., Hussey, J., Yen, S., Hardy, J. and Yen, S. H. (2000). Sensitization of neuronal cells to oxidative stress with mutated human alpha-synuclein. J Neurochem 75: 2546–2554.PubMedCrossRefGoogle Scholar
  59. Kopito, R. R. (2000). Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10: 524–530.PubMedCrossRefGoogle Scholar
  60. Langston, J. W., Sastry, S., Chan, P., Forno, L. S., Bolin, L. M. and Di Monte, D. A. (1998). Novel alpha-synuclein-immunoreactive proteins in brain samples from the Contursi kindred, Parkinson’s, and Alzheimer’s disease. Exp Neurol 154: 684–690.PubMedCrossRefGoogle Scholar
  61. Lashuel, H. A., Petre, B. M., Wall, J., Simon, M., Nowak, R. J., Walz, T. and Lansbury, P. T., Jr. (2002). Alpha-synuclein, especially the Parkinson’s disease-associated mutants, forms pore-like annular and tubular protofibrils. J Mol Biol 322: 1089–1102.PubMedCrossRefGoogle Scholar
  62. Lee, M., Hyun, D., Halliwell, B. and Jenner, P. (2001). Effect of the overexpression of wild-type or mutant alpha-synuclein on cell susceptibility to insult. J Neurochem 76: 998–1009.PubMedCrossRefGoogle Scholar
  63. Lee, H.-J. and Lee, S.-J. (2002). Characterization of cytoplasmic alpha-synuclein aggregates. Fibril formation is tightly linked to the inclusion-forming process in cells. J Biol Chem 277: 48976–48983.PubMedCrossRefGoogle Scholar
  64. Lee, H.-J., Choi, C. and Lee, S.-J. (2002a). 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.PubMedCrossRefGoogle Scholar
  65. Lee, H.-J., Shin, S. Y., Choi, C., Lee, Y. H. and Lee, S.-J. (2002b). Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors. J Biol Chem 277: 5411–5417.PubMedCrossRefGoogle Scholar
  66. Lee, S. J. (2003). alpha-Synuclein aggregation: a link between mitochondrial defects and Parkinson’s disease? Antioxid Redox Signal 5: 337–348.PubMedCrossRefGoogle Scholar
  67. Lee, H.-J., Khoshaghideh, F., Patel, S. and Lee, S.-J. (2004). Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci 24: 1888–1896.PubMedCrossRefGoogle Scholar
  68. Li, W., Lesuisse, C., Xu, Y., Troncoso, J. C., Price, D. L. and Lee, M. K. (2004). Stabilization of alpha-synuclein protein with aging and familial parkinson’s disease-linked A53T mutation. J Neurosci 24: 7400–7409.PubMedCrossRefGoogle Scholar
  69. Lindersson, E., Beedholm, R., Hojrup, P., Moos, T., Gai, W., Hendil, K. B. and Jensen, P. H. (2004). Proteasomal inhibition by alpha-synuclein filaments and oligomers. J Biol Chem 279: 12924–12934.PubMedCrossRefGoogle Scholar
  70. Liu, C. W., Corboy, M. J., DeMartino, G. N. and Thomas, P. J. (2003). Endoproteolytic activity of the proteasome. Science 299: 408–411.PubMedCrossRefGoogle Scholar
  71. Liu, S., Ninan, I., Antonova, I., Battaglia, F., Trinchese, F., Narasanna, A., Kolodilov, N., Dauer, W., Hawkins, R. D. and Arancio, O. (2004). alpha-Synuclein produces a long-lasting increase in neurotransmitter release. EMBO J 23: 4506–4516.PubMedCrossRefGoogle Scholar
  72. London, J., Skrzynia, C. and Goldberg, M. E. (1974). Renaturation of Escherichia coli tryptophanase after exposure to 8 M urea. Evidence for the existence of nucleation centers. Eur J Biochem 47: 409–415.PubMedCrossRefGoogle Scholar
  73. Manning-Bog, A. B., McCormack, A. L., Li, J., Uversky, V. N., Fink, A. L. and Di Monte, D. A. (2002). The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem 277: 1641–1644.PubMedCrossRefGoogle Scholar
  74. Manning-Bog, A. B., McCormack, A. L., Purisai, M. G., Bolin, L. M. and Di Monte, D. A. (2003). Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci 23: 3095–3099.PubMedGoogle Scholar
  75. Maries, E., Dass, B., Collier, T. J., Kordower, J. H. and Steece-Collier, K. (2003). The role of alpha-synuclein in Parkinson’s disease: insights from animal models. Nat Rev Neurosci 4: 727–738.PubMedCrossRefGoogle Scholar
  76. Maroteaux, L., Campanelli, J. T. and Scheller, R. H. (1988). Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8: 2804–2815.PubMedGoogle Scholar
  77. McNaught, K. S., Mytilineou, C., Jnobaptiste, R., Yabut, J., Shashidharan, P., Jennert, P. and Olanow, C. W. (2002). Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J Neurochem 81: 301–306.PubMedCrossRefGoogle Scholar
  78. Mishizen-Eberz, A. J., Guttmann, R. P., Giasson, B. I., Day, G. A., 3rd, Hodara, R., Ischiropoulos, H., Lee, V. M., Trojanowski, J. Q. and Lynch, D. R. (2003). Distinct cleavage patterns of normal and pathologic forms of alpha-synuclein by calpain I in vitro. J Neurochem 86: 836–847.PubMedCrossRefGoogle Scholar
  79. Norris, E. H., Giasson, B. I., Ischiropoulos, H. and Lee, V. M. (2003). Effects of oxidative and nitrative challenges on alpha-synuclein fibrillogenesis involve distinct mechanisms of protein modifications. J Biol Chem 278: 27230–27240.PubMedCrossRefGoogle Scholar
  80. Ostrerova, N., Petrucelli, L., Farrer, M., Mehta, N., Choi, P., Hardy, J. and Wolozin, B. (1999). alpha-Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci 19: 5782–5791.PubMedGoogle Scholar
  81. Park, S. M., Jung, H. Y., Kim, T. D., Park, J. H., Yang, C. H. and Kim, J. (2002). Distinct roles of the N-terminal-binding domain and the C-terminal solubilizing domain of alpha-synuclein, a molecular chaperone. J Biol Chem 277: 28512–28520.PubMedCrossRefGoogle Scholar
  82. Paxinou, E., Chen, Q., Weisse, M., Giasson, B. I., Norris, E. H., Rueter, S. M., Trojanowski, J. Q., Lee, V. M. and Ischiropoulos, H. (2001). Induction of alpha-synuclein aggregation by intracellular nitrative insult. J Neurosci 21: 8053–8061.PubMedGoogle Scholar
  83. Perrin, R. J., Woods, W. S., Clayton, D. F. and George, J. M. (2000). Interaction of human alpha-synuclein and Parkinson’s disease variants with phospholipids. Structural analysis using site-directed mutagenesis. J Biol Chem 275: 34393–34398.PubMedCrossRefGoogle Scholar
  84. Perrin, R. J., Woods, W. S., Clayton, D. F. and George, J. M. (2001). Exposure to long-chain polyunsaturated fatty acids triggers rapid multimerization of synucleins. J Biol Chem 11: 11.Google Scholar
  85. Petersen, K., Olesen, O. F. and Mikkelsen, J. D. (1999). Developmental expression of alpha-synuclein in rat hippocampus and cerebral cortex. Neuroscience 91: 651–659.PubMedCrossRefGoogle Scholar
  86. Petrucelli, L., O’Farrell, C., Lockhart, P. J., Baptista, M., Kehoe, K., Vink, L., Choi, P., Wolozin, B., Farrer, M., Hardy, J. and Cookson, M. R. (2002). Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36: 1007–1019.PubMedCrossRefGoogle Scholar
  87. Raghavan, R., Kruijff, L., Sterrenburg, M. D., Rogers, B. B., Hladik, C. L. and White, C. L., 3rd (2004). alpha-Synuclein expression in the developing human brain. Pediatr Dev Pathol 7: 506–516.PubMedCrossRefGoogle Scholar
  88. Rajan, R. S., Illing, M. E., Bence, N. F. and Kopito, R. R. (2001). Specificity in intracellular protein aggregation and inclusion body formation. Proc Natl Acad Sci USA 98: 13060–13065.PubMedCrossRefGoogle Scholar
  89. Rideout, H. J., Larsen, K. E., Sulzer, D. and Stefanis, L. (2001). Proteasomal inhibition leads to formation of ubiquitin/alpha-synuclein-immunoreactive inclusions in PC12 cells. J Neurochem 78: 899–908.PubMedCrossRefGoogle Scholar
  90. Saha, A. R., Ninkina, N. N., Hanger, D. P., Anderton, B. H., Davies, A. M. and Buchman, V. L. (2000). Induction of neuronal death by alpha-synuclein [In Process Citation]. Eur J Neurosci 12: 3073–3077.PubMedCrossRefGoogle Scholar
  91. Saudou, F., Finkbeiner, S., Devys, D. and Greenberg, M. E. (1998). Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95: 55–66.PubMedCrossRefGoogle Scholar
  92. Schluter, O. M., Fornai, F., Alessandri, M. G., Takamori, S., Geppert, M., Jahn, R. and Sudhof, T. C. (2003). Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice. Neuroscience 118: 985–1002.PubMedCrossRefGoogle Scholar
  93. Sharon, R., Bar-Joseph, I., Mirick, G. E., Serhan, C. N. and Selkoe, D. J. (2003). Altered fatty acid composition of dopaminergic neurons expressing alpha-synuclein and human brains with alpha-synucleinopathies. J Biol Chem 278: 49874–49881.PubMedCrossRefGoogle Scholar
  94. Snyder, H., Mensah, K., Theisler, C., Lee, J., Matouschek, A. and Wolozin, B. (2003). Aggregated and monomeric alpha-synuclein bind to the S6′ proteasomal protein and inhibit proteasomal function. J Biol Chem 278: 11753–11759.PubMedCrossRefGoogle Scholar
  95. Souza, J. M., Giasson, B. I., Lee, V. M. and Ischiropoulos, H. (2000). Chaperone-like activity of synucleins. FEBS Lett 474: 116–119.PubMedCrossRefGoogle Scholar
  96. Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M. and Goedert, M. (1998). alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci USA 95: 6469–6473.PubMedCrossRefGoogle Scholar
  97. Stefanis, L., Larsen, K. E., Rideout, H. J., Sulzer, D. and Greene, L. A. (2001). Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci 21: 9549–9560.PubMedGoogle Scholar
  98. Tanaka, Y., Engelender, S., Igarashi, S., Rao, R. K., Wanner, T., Tanzi, R. E., Sawa, A., V, L. D., Dawson, T. M. and Ross, C. A. (2001). Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum Mol Genet 10: 919–926.PubMedCrossRefGoogle Scholar
  99. Tanaka, M., Kim, Y. M., Lee, G., Junn, E., Iwatsubo, T., Mouradian, M. M. (2004) Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem 279: 4625–4631.PubMedCrossRefGoogle Scholar
  100. Taylor, J. P., Tanaka, F., Robitschek, J., Sandoval, C. M., Taye, A., Markovic-Plese, S. and Fischbeck, K. H. (2003). Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. Hum Mol Genet 12: 749–757.PubMedCrossRefGoogle Scholar
  101. Tofaris, G. K., Layfield, R. and Spillantini, M. G. (2001). alpha-Synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett 509: 22–26.PubMedCrossRefGoogle Scholar
  102. Tofaris, G. K., Razzaq, A., Ghetti, B., Lilley, K. S. and Spillantini, M. G. (2003). Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. J Biol Chem 278: 44405–44411.PubMedCrossRefGoogle Scholar
  103. Ueda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Yoshimoto, M., Otero, D. A., Kondo, J., Ihara, Y. and Saitoh, T. (1993). Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 90: 11282–11286.PubMedCrossRefGoogle Scholar
  104. Uversky, V. N., Gillespie, J. R. and Fink, A. L. (2000). Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins 41: 415–427.PubMedCrossRefGoogle Scholar
  105. Uversky, V. N., Li, J. and Fink, A. L. (2001a). Evidence for a partially folded intermediate in alpha-synuclein fibril formation. J Biol Chem 276: 10737–10744.PubMedCrossRefGoogle Scholar
  106. Uversky, V. N., Li, J. and Fink, A. L. (2001b). Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson’s disease and heavy metal exposure. J Biol Chem 276: 44284–44296.PubMedCrossRefGoogle Scholar
  107. Uversky, V. N., Lee, H.-J., Li, J., Fink, A. L. and Lee, S.-J. (2001c). Stabilization of partially folded conformation during {alpha}-synuclein oligomerization in both purified and cytosolic preparations. J Biol Chem 5: 5.Google Scholar
  108. Vila, M., Vukosavic, S., Jackson-Lewis, V., Neystat, M., Jakowec, M. and Przedborski, S. (2000). Alpha-synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin MPTP. J Neurochem 74: 721–729.PubMedCrossRefGoogle Scholar
  109. Volles, M. J. and Lansbury, P. T., Jr. (2002). Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson’s disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 41: 4595–4602.PubMedCrossRefGoogle Scholar
  110. Volles, M. J. and Lansbury, P. T., Jr. (2003). Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson’s disease. Biochemistry 42: 7871–7878.PubMedCrossRefGoogle Scholar
  111. Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N. and Rubinsztein, D. C. (2003). alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278: 25009–25013.PubMedCrossRefGoogle Scholar
  112. Weinreb, P. H., Zhen, W., Poon, A. W., Conway, K. A. and Lansbury, P. T., Jr. (1996). NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 35: 13709–13715.PubMedCrossRefGoogle Scholar
  113. Withers, G. S., George, J. M., Banker, G. A. and Clayton, D. F. (1997). Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons. Brain Res Dev Brain Res 99: 87–94.PubMedCrossRefGoogle Scholar
  114. Xu, J., Kao, S. Y., Lee, F. J., Song, W., Jin, L. W. and Yankner, B. A. (2002). Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat Med 8: 600–606.PubMedCrossRefGoogle Scholar
  115. Zhou, W., Hurlbert, M. S., Schaack, J., Prasad, K. N. and Freed, C. R. (2000). Overexpression of human alpha-synuclein causes dopamine neuron death in rat primary culture and immortalized mesencephalon-derived cells. Brain Res 866: 33–43.PubMedCrossRefGoogle Scholar
  116. Zhou, W., Schaack, J., Zawada, W. M. and Freed, C. R. (2002). Overexpression of human alpha-synuclein causes dopamine neuron death in primary human mesencephalic culture. Brain Res 926: 42–50.PubMedCrossRefGoogle Scholar
  117. Zhou, Y., Gu, G., Goodlett, D. R., Zhang, T., Pan, C., Montine, T. J., Montine, K. S., Aebersold, R. H. and Zhang, J. (2004). Analysis of alpha-synuclein-associated proteins by quantitative proteomics. J Biol Chem 279: 39155–39164.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Seung-Jae Lee
    • 1
  • Yoon Suk Kim
    • 1
  1. 1.The Parkinson’s InstituteSunnyvaleUSA

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