Journal of Molecular Neuroscience

, Volume 24, Issue 3, pp 343–352 | Cite as

The role of α-synuclein assembly and metabolism in the pathogenesis of Lewy body disease

  • Makoto Hashimoto
  • Kohichi Kawahara
  • Pazit Bar-On
  • Edward Rockenstein
  • Leslie Crews
  • Eliezer Masliah
Original Article


Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are members of a family of disorders characterized by the presence of inclusion bodies, or Lewy bodies (LBs), filled with aggregates of α-synuclein. These diseases are a leading cause of movement disorders and dementia in the aging population, and it is crucial to understand the factors leading to the accumulation and assembly of these α-synuclein aggregates. Previous studies have uncovered much about the factors leading to aggregation and the mechanisms causing neurotoxicity of these inclusion bodies; however, little is known about factors that promote the degradation and prevent the aggregation of α-synuclein. The present article provides a review of recent efforts in the investigation of factors involved in α-synuclein metabolism and the mechanisms involved in preventing accumulation of α-synuclein and degrading this molecule. Understanding these processes might provide targets for the development of novel therapies for disorders such as DLB and PD.

Index Entries

α-synuclein degradation metabolism Lewy bodies proteasom ubiquitin 


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  1. Auluck P. K. and N. M. Bonini (2002) Pharmacological prevention of Parkinson disease in Drosophila. Nat Med. 8, 1185–1186.PubMedCrossRefGoogle Scholar
  2. Auluck P. K., Chan H. Y., et al. (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295(5556), 865–868.PubMedCrossRefGoogle Scholar
  3. Bence N. F., Sampat R. M., et al. (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292, 1467–1468.CrossRefGoogle Scholar
  4. Bennett M. C., Bishop J. F., et al. (1999) Degradation of alpha-synuclein by proteasome. J. Biol. Chem. 274(48), 33,855–33,858.CrossRefGoogle Scholar
  5. Bond U., Agell N., et al. (1988) Ubiquitin in stressed chicken embryo fibroblasts. J. Biol. Chem. 263, 2384–2388.PubMedGoogle Scholar
  6. Borden K. L. and Freemont P. S. (1996) The RING finger domain: a recent example of a sequence-structure family. Curr. Opin, Struct. Biol. 6, 395–401.CrossRefGoogle Scholar
  7. Chung K. K., Zhang Y., et al. (2001) Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat. Med. 7, 1144–1150.PubMedCrossRefGoogle Scholar
  8. Conway K., Harper J., et al. (1998) Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat. Med. 4, 1318–1320.PubMedCrossRefGoogle Scholar
  9. Cummings C. J., Mancini M. A., et al. (1998) Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat. Genet. 19, 148–154.PubMedCrossRefGoogle Scholar
  10. Cummings C. J., Sun Y., et al. (2001) Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum. Mol. Genet. 10, 1511–1518.PubMedCrossRefGoogle Scholar
  11. Dikic I. (2003) Mechanisms controlling EGF receptor endocytosis and degradation. Biochem. Soc. Trans. 31(Pt. 6), 1178–1181.PubMedCrossRefGoogle Scholar
  12. Feany M. and Bender W. (2000) A Drosophila model of Parkinson’s disease. Nature 404, 394–398.PubMedCrossRefGoogle Scholar
  13. Fink A. L. (1999) Chaperone-mediated protein folding. Physiol. Rev. 79, 425–449.PubMedGoogle Scholar
  14. Finley D., Ozkaynak E., et al. (1987) The yeast polyubiquitin gene is essential for resistance to high temperatures, starvation, and other stresses. Cell 48, 1035–1046.PubMedCrossRefGoogle Scholar
  15. Ghee M., Fournier A., et al. (2000) Rat alpha-synuclein interacts with Tat binding protein 1, a component of the 26S proteasomal complex. J. Neurochem. 75, 2221–2224.PubMedCrossRefGoogle Scholar
  16. Giasson B. I., Duda J. E., et al. (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing a53t human alpha-synuclein. Neuron 34(4), 521–533.PubMedCrossRefGoogle Scholar
  17. Glabe C. (2001) Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease. J. Mol. Neurosci. 17, 137–145.PubMedCrossRefGoogle Scholar
  18. Grune T., Merker K., et al. (2003) Selective degradation of oxidatively modified protein substrates by the proteasome. Biochem. Biophys. Res. Commun. 305, 709–718.PubMedCrossRefGoogle Scholar
  19. Haglund K., Di Fiore P. P., et al. (2003) Distinct monoubiquitin signals in receptor endocytosis. Trends Biochem. Sci. 28, 598–603.PubMedCrossRefGoogle Scholar
  20. Hashimoto M., Bar-On P., Ho G., Takenouchi T., Rockenstein E., Crews L., Masliah E., (2004) β-synuclein regulates Akt activity in neuronal cells. A possible mechanism for neuroprotection in Parkinson’s disease. J. Biol. Chem. 279(22), 23,622–23,629.CrossRefGoogle Scholar
  21. Hashimoto M., Rockenstein E., et al. (2003) Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases. Neuromol. Med. 4(1,2), 21–36.CrossRefGoogle Scholar
  22. Hashimoto M., Rockenstein E., et al. (2001) β-Synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron 32(2), 213–223.PubMedCrossRefGoogle Scholar
  23. Imai Y., Soda M., et al. (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105, 891–902.PubMedCrossRefGoogle Scholar
  24. Iqbal K. and Grundke-Iqbal I. (1991) Ubiquitination and abnormal phosphorylation of paired helical filaments in Alzheimer’s disease. Mol. Neurobiol. 5, 399–410.PubMedCrossRefGoogle Scholar
  25. Irizarry M., Growdon W., et al. (1998) Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson’s disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity. J. Neuropathol. Exp. Neurol. 57, 334–337.PubMedGoogle Scholar
  26. Ischiropoulos H. (2003) Oxidative modifications of alpha-synuclein. Ann. N. Y. Acad. Sci. 991, 93–100.PubMedCrossRefGoogle Scholar
  27. Iwai A. (2000) Properties of NACP/alpha-synuclein and its role in Alzheimer’s disease. Biochim. Biophys. Acta 1502, 95–109.PubMedGoogle Scholar
  28. Iwata A., Maruyama M., et al. (2003) Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies. Hum. Mol. Genet. 12, 2625–2635.PubMedCrossRefGoogle Scholar
  29. Kanda S., Bishop J. F., et al. (2000) Enhanced vulnerability to oxidative stress by alpha-synuclein mutations and C-terminal truncation. Neuroscience 97, 279–284.PubMedCrossRefGoogle Scholar
  30. Kim J. H., Park K. C., et al. (2003) Deubiquitinating enzymes as cellular regulators. J. Biochem. (Tokyo) 134, 9–18.Google Scholar
  31. Kim S. J., Sung J. Y., et al. (2003) Parkin cleaves intracellular alpha-synuclein inclusions via the activation of calpain. J. Biol. Chem. 278, 41,890–41,899.Google Scholar
  32. Kitada T., Asakawa S., et al. (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608.PubMedCrossRefGoogle Scholar
  33. Klucken J., Shin Y., Masliah E., Hyman B. T., and McLean P. J., (2004) Hsp70 reduces α-synuclein aggregation and toxicity. J. Biol. Chem. 279(24), 25,497–25,502.CrossRefGoogle Scholar
  34. Kruger R., Kuhn W., et al. (1998) Ala30Pro mutation in the gene encoding α-synuclein in Parkinsons’s disease. Nat. Genet. 18, 106–108.PubMedCrossRefGoogle Scholar
  35. Kuzuhara S., Mori H., et al. (1988) Lewy bodies are ubiquinated. A light and electron microscopic immunocytochemical study. Acta Neuropathol. 75, 345–353.PubMedCrossRefGoogle Scholar
  36. Lee G., Junn E., et al. (2002) Synphilin-1 degradation by the ubiquitin-proteasome pathway and effects on cell survival. J. Neurochem. 83, 346–352.PubMedCrossRefGoogle Scholar
  37. Lee M. S. and Tsai L. H. (2003) Cdk5: one of the links between senile plaques and neurofibrillary tangles? J. Alzheimers Dis. 5, 127–137.PubMedGoogle Scholar
  38. Leroy E., Boyer R., et al. (1998) The ubiquitin pathway in Parkinsons’s disease. Nature 395, 451–452.PubMedCrossRefGoogle Scholar
  39. Liu Y., Fallon L., et al. (2002) The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson’s disease susceptibility. Cell 111, 209–218.PubMedCrossRefGoogle Scholar
  40. Marchese A., Raiborg C., et al. (2003) The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G protein-coupled receptor CXCR4. Dev. Cell 5, 709–722.PubMedCrossRefGoogle Scholar
  41. Masliah E., Iwai A., et al. (1996) Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer’s disease. Am. J. Pathol. 148, 201–210.PubMedGoogle Scholar
  42. Masliah E., Rockenstein E., et al. (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: Implications for neurodegenerative disorders. Science 287, 1265–1269.PubMedCrossRefGoogle Scholar
  43. Masliah E., Rockenstein E., et al. (2001) β amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model likning Alzheimer’s and Parkinson’s disease. Proc. Natl. Acad. Sci. U.S.A. 98, 12,245–12,250.CrossRefGoogle Scholar
  44. McKeith I. G. (2000) Spectrum of Parkinson’s disease, Parkinson’s dementia, and Lewy body dementia. Neurol. Clin. 18, 865–902.PubMedCrossRefGoogle Scholar
  45. McNaught K. and Jenner P. (2001) Proteasomal function is impared in substantial nigra in Parkinson’s disease. Neurosci. Lett. 297, 191–194.PubMedCrossRefGoogle Scholar
  46. Mishizen-Eberz A. J., Guttmann R. P., et al. (2003) Distinct cleavage patterns of normal and pathologic forms of alpha-synuclein by calpain I in vitro. J. Neurochem. 86, 836–847.PubMedCrossRefGoogle Scholar
  47. Mosesson Y., Shtiegman K., et al. (2003) Endocytosis of receptor tyrosine kinases is driven by monoubiquitylation, not polyubiquitylation. J. Biol. Chem. 278, 21,323–21,326.CrossRefGoogle Scholar
  48. Narayanan V. and Scarlata S. (2001) Membrane binding and self-association of alpha-synucleins. Biochemistry 40, 9927–9934.PubMedCrossRefGoogle Scholar
  49. Narhi L., Wood S. J., et al. (1999) Both familial Parkinson’s disease mutations accelerate alpha-synuclein aggregation. J. Biol. Chem. 274, 9843–9846.PubMedCrossRefGoogle Scholar
  50. Ogawa K., Yamada T., et al. (2000) Localization of a novel type trypsin-like serine protease, neurosin, in brain tissues of Alzheimer’s disease and Parkinson’s disease. Psychiatry Clin. Neurosci. 54, 419–426.PubMedCrossRefGoogle Scholar
  51. Orth M. and Schapira A. H. (2001) Mitochondria and degenerative disorders. Am. J. Med. Genet. 106, 27–36.PubMedCrossRefGoogle Scholar
  52. Osterova-Golts N., Petrucelli L., et al. (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J. Neurosci. 20, 6048–6054.Google Scholar
  53. Paxinou E., Chen Q., et al. (2001) Induction of alpha-synuclein aggregation by intracellular nitrative insult. J. Neurosci. 21, 8053–8061.PubMedGoogle Scholar
  54. Perrin R., Woods W., et al. (2000) Interaction of human alpha-synuclein and Parkinson’s disease variants with phospholipids: structural analysis using site-directed mutagenesis. J. Biol. Chem. 275, 34,393–34,398.CrossRefGoogle Scholar
  55. Pickart C. M. (2001) Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70, 503–533.PubMedCrossRefGoogle Scholar
  56. Polymeropoulos M., Lavedan C., et al. (1997) Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047.PubMedCrossRefGoogle Scholar
  57. Saigoh K., Wang Y. L., et al. (1999) Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. Nat. Genet. 23, 47–51.PubMedGoogle Scholar
  58. Sampathu D. M., Giasson B. I., et al. (2003) Ubiquitination of alpha-synuclein is not required for formation of pathological inclusions in alpha-synucleinopathies. Am. J. Pathol. 163, 91–100.PubMedGoogle Scholar
  59. Sharon R., Goldberg M. S., et al. (2001) alpha-Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids, and shows homology to the fatty acid-binding proteins. Proc. Natl. Acad. Sci. U.S.A. 98, 9110–9115.PubMedCrossRefGoogle Scholar
  60. Shenoy S. K., McDonald P. H., et al. (2001) Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science 294, 1307–1313.PubMedCrossRefGoogle Scholar
  61. Shimura H., Hattori N., et al. (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat. Genet. 25, 302–305.PubMedCrossRefGoogle Scholar
  62. Shimura H., Schlossmacher M. G., et al. (2001) Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson’s disease. Science 293, 263–269.PubMedCrossRefGoogle Scholar
  63. Snyder H., Mensah K., et al. (2003) Aggregated and monomeric alpha-synuclein bind to the S6′ proteasomal protein and inhibit proteasomal function. J. Biol. Chem. 278, 11,753–11,759.Google Scholar
  64. Souza J., Giasson B., et al. (2000) Chaperone-like activity of synucleins. FEBS Lett. 474, 116–119.PubMedCrossRefGoogle Scholar
  65. Spillantini M., Crowther R., et al. (1998) Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc. Natl. Acad. Sci. U.S.A. 95, 6469–6473.PubMedCrossRefGoogle Scholar
  66. Spillantini M., Schmidt M., et al. (1997) α-Synuclein in Lewy bodies. Nature 388, 839,840.PubMedCrossRefGoogle Scholar
  67. Staropoli J., McDermott C., et al. (2003) Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron 37, 735–749.PubMedCrossRefGoogle Scholar
  68. Takeda A., Hashimoto M., et al. (1998a) Abnormal distribution of the non-Aβ component of Alzheimer’s disease amyloid precursor/α-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment. Lab. Invest. 78, 1169–1177.PubMedGoogle Scholar
  69. Takeda A., Mallory M., et al. (1998b) Abnormal accumulation of NACP/α-synuclein in neurodegenerative disorders. Am. J. Pathol. 152, 367–372.PubMedGoogle Scholar
  70. Tofaris G. K., Layfield R., et al. (2001) α-Synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett. 509, 22–26.PubMedCrossRefGoogle Scholar
  71. Trojanowski J. and Lee V. (1998) Aggregation of neurofilament and alpha-synuclein proteins in Lewy bodies: implications for pathogenesis of Parkinson disease and Lewy body dementia. Arch. Neurol. 55, 151–152.PubMedCrossRefGoogle Scholar
  72. Ueda K., Masliah E., et al. (1993) Novel amyloid component (NAC) differentiates Alzheimer’s disease from normal aging plaques. Soc. Neurosci. Abstr. 19, 1254.Google Scholar
  73. Uversky V. N., Li J., et al. (2002) Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins. J. Biol. Chem. 277, 11,970–11,978.CrossRefGoogle Scholar
  74. Volles M. J., Lee S. J., et al. (2001) Vesicle permeabilization by protofibrillar alpha-synuclein: implications for the pathogenesis and treatment of Parkinson’s disease. Biochemistry 40, 7812–7819.PubMedCrossRefGoogle Scholar
  75. Wakabayashi K., Hansen L., et al. (1997) Neurofibrillary tangles in the dentate granule cells in Alzheimer’s disease, Lewy body disease and progressive supranuclear palsy. Acta Neuropathol. 93, 7–12.PubMedCrossRefGoogle Scholar
  76. Warrick J. M., Chan H. Y., et al. (1999) Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat. Genet. 23, 425–428.PubMedCrossRefGoogle Scholar
  77. Weinreb P., Zhen W., et al. (1996) NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 35, 13,709–13,715.CrossRefGoogle Scholar
  78. Yamazaki T., Haass C., et al. (1997) Specific increase in amyloid beta-protein 42 secretion ratio by calpain inhibition. Biochemistry 36, 8377–8383.PubMedCrossRefGoogle Scholar
  79. Yamin G., Glaser C. B., et al. (2003) Certain metals trigger fibrillation of methionine-oxidized alpha-synuclein. J. Biol. Chem. 278, 27,360–27,365.CrossRefGoogle Scholar
  80. Yang Y., Nishimura I., et al. (2003) Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron 37, 911–924.PubMedCrossRefGoogle Scholar
  81. Zarghooni M., Soosaipillai A., et al. (2002) Decreased concentration of human kallikrein 6 in brain extracts of Alzheimer’s disease patients. Clin Biochem. 35, 225–231.PubMedCrossRefGoogle Scholar
  82. Zhang Y., Gao J., et al. (2000) Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc. Natl. Acad. Sci. U.S.A. 97, 13,354–13,359.Google Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Makoto Hashimoto
    • 1
  • Kohichi Kawahara
    • 1
  • Pazit Bar-On
    • 1
  • Edward Rockenstein
    • 1
  • Leslie Crews
    • 1
  • Eliezer Masliah
    • 1
    • 2
  1. 1.Department of NeurosciencesUniversity of California San DiegoLa Jolla
  2. 2.Department of PathologyUniversity of California San DiegoLa Jolla

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