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Origins and Effects of Extracellular α-synuclein: Implications in Parkinson’s Disease

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Abstract

Misfolding and abnormal aggregation of the neuronal protein α-synuclein has been implicated in the pathogenesis of Parkinson’s disease and related neurological disorders, such as dementia with Lewy bodies. α-synuclein is a conventional cytosolic protein and is thought to exert its pathogenic function exclusively in the neuronal cytoplasm in a cell-autonomous manner. However, the current model is being challenged by a series of new observations that demonstrate the presence of α-synuclein and its aggregated forms in the extracellular fluid both in vivo and in vitro. Extracellular α-synuclein appears to be delivered by unconventional exocytosis of intravesicular α-synuclein, although the exact mechanism has not been characterized. Compared to the cytosolic α-synuclein, intravesicular α-synuclein is prone to aggregation and the potential source of extracellular aggregates. A number of tissue culture studies suggest that exposure to extracellular α-synuclein aggregates induces microglial activation, release of pro-inflammatory cytokines from astrocytes, and neurotoxicity. Thus, exocytosis of α-synuclein may be an important mechanism for amplifying and spreading degenerative changes from a small group of cells to its surrounding tissues, and it potentially provides therapeutic targets for halting the progression of the disease.

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References

  • Ahn, K. J., Paik, S. R., Chung, K. C., & Kim, J. (2006). Amino acid sequence motifs and mechanistic features of the membrane translocation of alpha-synuclein. Journal of Neurochemistry, 97, 265–279.

    Article  PubMed  CAS  Google Scholar 

  • Albani, D., Peverelli, E., Rametta, R., Batelli, S., Veschini, L., Negro, A., et al. (2004). Protective effect of TAT-delivered alpha-synuclein: Relevance of the C-terminal domain and involvement of HSP70. FASEB Journal, 18, 1713–1715.

    PubMed  CAS  Google Scholar 

  • Bodles, A. M., Guthrie, D. J., Harriott, P., Campbell, P., & Irvine, G. B. (2000). Toxicity of non-Abeta component of Alzheimer’s disease amyloid, and N-terminal fragments thereof, correlates to formation of beta-sheet structure and fibrils. European Journal of Biochemistry, 267, 2186–2194.

    Article  PubMed  CAS  Google Scholar 

  • Borghi, R., Marchese, R., Negro, A., Marinelli, L., Forloni, G., Zaccheo, D., et al. (2000). Full length alpha-synuclein is present in cerebrospinal fluid from Parkinson’s disease and normal subjects. Neuroscience Letters, 287, 65–67.

    Article  PubMed  CAS  Google Scholar 

  • Braak, H., Ghebremedhin, E., Rub, U., Bratzke, H., & Del Tredici, K. (2004). Stages in the development of Parkinson’s disease-related pathology. Cell & Tissue Research, 318, 121–134.

    Article  Google Scholar 

  • Caughey, B. (2000). Transmissible spongiform encephalopathies, amyloidoses and yeast prions: Common threads? Nature Medicine, 6, 751–754.

    Article  PubMed  CAS  Google Scholar 

  • Chartier-Harlin, M. C., Kachergus, J., Roumier, C., Mouroux, V., Douay, X., Lincoln, S., et al. (2004). Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet, 364, 1167–1169.

    Article  PubMed  CAS  Google Scholar 

  • Cohlberg, J. A., Li, J., Uversky, V. N., & Fink, A. L. (2002). Heparin and other glycosaminoglycans stimulate the formation of amyloid fibrils from alpha-synuclein in vitro. Biochemistry, 41, 1502–1511.

    Article  PubMed  CAS  Google Scholar 

  • Conway, K. A., Lee, S.-J., Rochet, J. C., Ding, T. T., Williamson, R. E., & Lansbury Jr., P. T. (2000). 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. Proceedings of the National Academy of Sciences of the United States of America, 97, 571–576.

    Article  PubMed  CAS  Google Scholar 

  • Du, H. N., Tang, L., Luo, X. Y., Li, H. T., Hu, J., Zhou, J. W., et al. (2003). A peptide motif consisting of glycine, alanine, and valine is required for the fibrillization and cytotoxicity of human alpha-synuclein. Biochemistry, 42, 8870–8878.

    Article  PubMed  CAS  Google Scholar 

  • El-Agnaf, O. M., Jakes, R., Curran, M. D., Middleton, D., Ingenito, R., Bianchi, E., et al. (1998). Aggregates from mutant and wild-type alpha-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of beta-sheet and amyloid-like filaments. FEBS Letters, 440, 71–75.

    Article  PubMed  CAS  Google Scholar 

  • El-Agnaf, O. M., Salem, S. A., Paleologou, K. E., Cooper, L. J., Fullwood, N. J., Gibson, M. J., et al. (2003). Alpha-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB Journal, 17, 1945–1947.

    PubMed  CAS  Google Scholar 

  • El-Agnaf, O. M., Salem, S. A., Paleologou, K. E., Curran, M. D., Gibson, M. J., Court, J. A., et al. (2006). Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. FASEB Journal, 20, 419–425.

    Article  PubMed  CAS  Google Scholar 

  • Fahn, S., & Sulzer, D. (2004). Neurodegeneration and neuroprotection in Parkinson disease. NeuroRx, 1, 139–154.

    Article  PubMed  Google Scholar 

  • Fevrier, B., & Raposo, G. (2004). Exosomes: Endosomal-derived vesicles shipping extracellular messages. Current Opinion in Cell Biology, 16, 415–421.

    Article  PubMed  CAS  Google Scholar 

  • Forloni, G., Bertani, I., Calella, A. M., Thaler, F., & Invernizzi, R. (2000). Alpha-synuclein and Parkinson’s disease: Selective neurodegenerative effect of alpha-synuclein fragment on dopaminergic neurons in vitro and in vivo. Annals of Neurology, 47, 632–640.

    Article  PubMed  CAS  Google Scholar 

  • Forno, L. S. (1996). Neuropathology of Parkinson’s disease. Journal of Neuropathology and Experimental Neurology, 55, 259–272.

    PubMed  CAS  Google Scholar 

  • Fortin, D. L., Nemani, V. M., Voglmaier, S. M., Anthony, M. D., Ryan, T. A., Edwards, R. H. (2005). Neural activity controls the synaptic accumulation of {alpha}-synuclein. Journal of Neuroscience, 25, 10913–10921.

    Article  PubMed  CAS  Google Scholar 

  • Greenbaum, E. A., Graves, C. L., Mishizen-Eberz, A. J., Lupoli, M. A., Lynch, D. R., Englander, S. W., et al. (2005). The E46K mutation in alpha-synuclein increases amyloid fibril formation. Journal of Biological Chemistry, 280, 7800–7807.

    Article  PubMed  CAS  Google Scholar 

  • Hoyer, W., Antony, T., Cherny, D., Heim, G., Jovin, T. M., & Subramaniam, V. (2002). Dependence of alpha-synuclein aggregate morphology on solution conditions. Journal of Molecular Biology, 322, 383–393.

    Article  PubMed  CAS  Google Scholar 

  • Ibanez, P., Bonnet, A. M., Debarges, B., Lohmann, E., Tison, F., Pollak, P., et al. (2004). Causal relation between alpha-synuclein gene duplication and familial Parkinson’s disease. Lancet, 364, 1169–1171.

    Article  PubMed  CAS  Google Scholar 

  • Kayed, R., Sokolov, Y., Edmonds, B., McIntire, T. M., Milton, S. C., Hall, J. E., et al. (2004). Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. Journal of Biological Chemistry, 279, 46363–46366.

    Article  PubMed  CAS  Google Scholar 

  • Kim, Y. S., Laurine, E., Woods, W., & Lee, S. J. (2006). A novel mechanism of interaction between alpha-synuclein and biological membranes. Journal of Molecular Biology, 360, 386–397.

    Article  PubMed  CAS  Google Scholar 

  • Klegeris, A., Giasson, B. I., Zhang, H., Maguire, J., Pelech, S., & McGeer, P. L. (2006). Alpha-synuclein and its disease-causing mutants induce ICAM-1 and IL-6 in human astrocytes and astrocytoma cells. FASEB Journal, 20, 2000–2008.

    Article  PubMed  CAS  Google Scholar 

  • Kruger, R., Kuhn, W., Muller, T., Woitalla, D., Graeber, M., Kosel, S., et al. (1998). Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nature Genetics, 18, 106–108.

    Article  PubMed  CAS  Google Scholar 

  • Lee, E. N., Cho, H. J., Lee, C. H., Lee, D., Chung, K. C., & Paik, S. R. (2004). Phthalocyanine tetrasulfonates affect the amyloid formation and cytotoxicity of alpha-synuclein. Biochemistry, 43, 3704–3715.

    Article  PubMed  CAS  Google Scholar 

  • Lee, H. J., Patel, S., & Lee, S. J. (2005). Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. Journal of Neuroscience, 25, 6016–6024.

    Article  PubMed  CAS  Google Scholar 

  • Lee, P. H., Lee, G., Park, H. J., Bang, O. Y., Joo, I. S., & Huh, K. (2006). The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy. Journal of Neural Transmission, 113, 1435–1439.

    Article  PubMed  CAS  Google Scholar 

  • Lowe, R., Pountney, D. L., Jensen, P. H., Gai, W. P., & Voelcker, N. H. (2004). Calcium(II) selectively induces alpha-synuclein annular oligomers via interaction with the C-terminal domain. Protein Science, 13, 3245–3252.

    Article  PubMed  CAS  Google Scholar 

  • Maries, E., Dass, B., Collier, T. J., Kordower, J. H., & Steece-Collier, K. (2003). The role of alpha-synuclein in Parkinson’s disease: Insights from animal models. Nature Reviews Neuroscience, 4, 727–738.

    Article  PubMed  CAS  Google Scholar 

  • Masliah, E., Rockenstein, E., Adame, A., Alford, M., Crews, L., Hashimoto, M., et al. (2005). Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. Neuron, 46, 857–868.

    Article  PubMed  CAS  Google Scholar 

  • Meyer-Luehmann, M., Coomaraswamy, J., Bolmont, T., Kaeser, S., Schaefer, C., Kilger, E., et al. (2006). Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science, 313, 1781–1784.

    Article  PubMed  CAS  Google Scholar 

  • Nickel, W. (2003). The mystery of nonclassical protein secretion. A current view on cargo proteins and potential export routes. European Journal of Biochemistry, 270, 2109–2119.

    Article  PubMed  CAS  Google Scholar 

  • Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., et al. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science, 276, 2045–2047.

    Article  PubMed  CAS  Google Scholar 

  • Seo, J. H., Rah, J. C., Choi, S. H., Shin, J. K., Min, K., Kim, H. S., et al. (2002). Alpha-synuclein regulates neuronal survival via Bcl-2 family expression and PI3/Akt kinase pathway. FASEB Journal, 16, 1826–1828.

    PubMed  CAS  Google Scholar 

  • Singleton, A. B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., et al. (2003). alpha-Synuclein locus triplication causes Parkinson’s disease. Science, 302, 841.

    Article  PubMed  CAS  Google Scholar 

  • Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M., Goedert, M. (1998). alpha-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, 95, 6469–6473.

    Article  PubMed  CAS  Google Scholar 

  • Sung, J. Y., Kim, J., Paik, S. R., Park, J. H., Ahn, Y. S., & Chung, K. C. (2001). Induction of neuronal cell death by Rab5A-dependent endocytosis of alpha-synuclein. Journal of Biological Chemistry, 276, 27441–27448.

    Article  PubMed  CAS  Google Scholar 

  • Sung, J. Y., Park, S. M., Lee, C. H., Um, J. W., Lee, H. J., Kim, J., et al. (2005). Proteolytic cleavage of extracellular secreted {alpha}-synuclein via matrix metalloproteinases. Journal of Biological Chemistry, 280, 25216–25224.

    Article  PubMed  CAS  Google Scholar 

  • Tokuda, T., Salem, S. A., Allsop, D., Mizuno, T., Nakagawa, M., Qureshi, M. M., et al. (2006). Decreased alpha-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson’s disease. Biochemical and Biophysical Research Communications, 349, 162–166.

    Article  PubMed  CAS  Google Scholar 

  • Volles, M. J., & Lansbury Jr., P. T. (2003). Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson’s disease. Biochemistry, 42, 7871–7878.

    Article  PubMed  CAS  Google Scholar 

  • Volles, M. J., Lee, S.-J., Rochet, J. C., Shtilerman, M. D., Ding, T. T., Kessler, J. C., et al. (2001). Vesicle permeabilization by protofibrillar alpha-synuclein: Implications for the pathogenesis and treatment of Parkinson’s disease. Biochemistry, 40, 7812–7819.

    Article  PubMed  CAS  Google Scholar 

  • Zarranz, J. J., Alegre, J., Gomez-Esteban, J. C., Lezcano, E., Ros, R., Ampuero, I., et al. (2004). The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Annals of Neurology, 55, 164–173.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, W., Wang, T., Pei, Z., Miller, D. S., Wu, X., Block, M. L., et al. (2005). Aggregated alpha-synuclein activates microglia: A process leading to disease progression in Parkinson’s disease. FASEB Journal, 19, 533–542.

    Article  PubMed  CAS  Google Scholar 

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  1. Center for Geriatric Neuroscience Research, Institute of Biomedical Science and Technology, Department of Biomedical Science and Technology, Konkuk University, Seoul, 143-701, Republic of Korea

    Seung-Jae Lee

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Lee, SJ. Origins and Effects of Extracellular α-synuclein: Implications in Parkinson’s Disease. J Mol Neurosci 34, 17–22 (2008). https://doi.org/10.1007/s12031-007-0012-9

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