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α-Synuclein Promotes the Recruitment of Tau to Protein Inclusions in Oligodendroglial Cells: Effects of Oxidative and Proteolytic Stress

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α-Synuclein is the major building block of cytoplasmic inclusions in neurodegenerative disorders named synucleinopathies. These inclusion bodies often contain the small heat shock protein αB-crystallin and the microtubule-associated protein tau. Oxidative modification of α-synuclein has been linked to fibril formation, and α-synuclein aggregation may induce the fibrillization of tau. To study α-synuclein aggregate formation, we have engineered oligodendroglial cells (OLN-93 cells) to stably express the longest human isoform of tau and wild-type α-synuclein or the A53T α-synuclein mutation. Under normal growth conditions, small punctuated α-synuclein aggregates were formed, which were more abundant in cells expressing the A53T mutation. After exposure to oxidative stress, protein inclusions were enlarged and were positive for thioflavin S, but the solubility of α-synuclein was not altered. Oxidative stress followed by proteasomal inhibition caused the occurrence of larger thioflavin S-positive inclusions, immunoreactive for tau and αB-crystallin, thus resembling glial cell inclusion bodies. Furthermore, this double stress situation led to a decrease in α-synuclein solubility, and αB-crystallin and HSP90 were present in the insoluble fraction. The formation and recruitment of tau to thioflavin S-positive protein aggregates in OLN-93 cells only expressing tau in the absence of α-synuclein, either after oxidative or proteasomal stress or both, was not observable. The data indicate that oxidatively modified α-synuclein is degraded by the proteasome and that it plays a pro-aggregatory role for tau in this cell culture model system.

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References

  • Auluck, P. K., Chan, H. Y., Trojanowski, J. Q., Lee, V. M., & Bonini, N. M. (2002). Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science, 295, 865–868. doi:10.1126/science.1067389.

    Article  PubMed  CAS  Google Scholar 

  • Bandhyopadhyay, U., & Cuervo, A. M. (2007). Chaperone-mediated autophagy in aging and neurodegeneration: Lessons from alpha-synuclein. Experimental Gerontology, 42, 120–128. doi:10.1016/j.exger.2006.05.019.

    Article  PubMed  CAS  Google Scholar 

  • Burn, D., & Jaros, E. (2001). Multiple system atrophy: Cellular and molecular pathology. Molecular Pathology, 54, 419–426.

    PubMed  CAS  Google Scholar 

  • Cairns, N. J., Atkinson, P. F., Hanger, D. P., Anderton, B. H., Daniel, S. E., & Lantos, P. L. (1997). Tau protein in the glial cytoplasmic inclusions of multiple system atrophy can be distinguished from abnormal tau in Alzheimer’s disease. Neuroscience Letters, 230, 49–52. doi:10.1016/S0304-3940(97)00474-6.

    Article  PubMed  CAS  Google Scholar 

  • Caughey, B., & Lansbury, P. T. (2003). Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annual Review of Neuroscience, 26, 267–298. doi:10.1146/annurev.neuro.26.010302.081142.

    Article  PubMed  CAS  Google Scholar 

  • Chin, S. S., & Goldman, J. E. (1996). Glial inclusions in CNS degenerative diseases. Journal of Neuropathology and Experimental Neurology, 55, 499–508. doi:10.1097/00005072-199605000-00001.

    Article  PubMed  CAS  Google Scholar 

  • Ciechanover, A., & Brundin, P. (2003). The ubiquitin proteasome system in neurodegenerative diseases: Sometimes the chicken, sometimes the egg. Neuron, 40, 427–446. doi:10.1016/S0896-6273(03)00606-8.

    Article  PubMed  CAS  Google Scholar 

  • Crystal, A. S., Giasson, B. I., Crowe, A., et al. (2003). A comparison of amyloid fibrillogenesis using the novel fluorescent compound K114. Journal of Neurochemistry, 86, 1359–1368. doi:10.1046/j.1471-4159.2003.01949.x.

    Article  PubMed  CAS  Google Scholar 

  • Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T., & Sulzer, D. (2004). Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science, 305, 1292–1295. doi:10.1126/science.1101738.

    Article  PubMed  CAS  Google Scholar 

  • Dabir, D. V., Trojanowski, J. Q., Richter-Landsberg, C., Lee, V. M., & Forman, M. S. (2004). Expression of the small heat-shock protein alphaB-crystallin in tauopathies with glial pathology. American Journal of Pathology, 164, 155–166.

    PubMed  CAS  Google Scholar 

  • Dedmon, M. M., Christodoulou, J., Wilson, M. R., & Dobson, C. M. (2005). Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species. The Journal of Biological Chemistry, 280, 14733–14740. doi:10.1074/jbc.M413024200.

    Article  PubMed  CAS  Google Scholar 

  • Forman, M. S., Trojanowski, J. Q., & Lee, V. M. (2004). Neurodegenerative diseases: A decade of discoveries paves the way for therapeutic breakthroughs. Nature Medicine, 10, 1055–1063. doi:10.1038/nm1113.

    Article  PubMed  CAS  Google Scholar 

  • Galpern, W. R., & Lang, A. E. (2006). Interface between tauopathies and synucleinopathies: A tale of two proteins. Annals of Neurology, 59, 449–458. doi:10.1002/ana.20819.

    Article  PubMed  CAS  Google Scholar 

  • Giasson, B. I., Forman, M. S., Higuchi, M., et al. (2003). Initiation and synergistic fibrillization of tau and alpha-synuclein. Science, 300, 636–640. doi:10.1126/science.1082324.

    Article  PubMed  CAS  Google Scholar 

  • Goedert, M. (2001). Alpha-synuclein and neurodegenerative diseases. Nature Reviews. Neuroscience, 2, 492–501. doi:10.1038/35081564.

    Article  PubMed  CAS  Google Scholar 

  • Goldbaum, O., Oppermann, M., Handschuh, M., et al. (2003). Proteasome inhibition stabilizes tau inclusions in oligodendroglial cells that occur after treatment with okadaic acid. The Journal of Neuroscience, 23, 8872–8880.

    PubMed  CAS  Google Scholar 

  • Goldberg, M. S., & Lansbury Jr., P. T. (2000). Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson’s disease? Nature Cell Biology, 2, E115–E119. doi:10.1038/35041081.

    Article  PubMed  CAS  Google Scholar 

  • Ischiropoulos, H. (2003). Oxidative modifications of alpha-synuclein. Annals of the New York Academy of Sciences, 991, 93–100.

    Article  PubMed  CAS  Google Scholar 

  • Ito, H., Kamei, K., Iwamoto, I., et al. (2002). Inhibition of proteasomes induces accumulation, phosphorylation, and recruitment of HSP27 and alphaB-crystallin to aggresomes. Journal of Biochemistry, 131, 593–603.

    PubMed  CAS  Google Scholar 

  • Kanda, S., Bishop, J. F., Eglitis, M. A., Yang, Y., & Mouradian, M. M. (2000). Enhanced vulnerability to oxidative stress by alpha-synuclein mutations and C-terminal truncation. Neuroscience, 97, 279–284. doi:10.1016/S0306-4522(00)00077-4.

    Article  PubMed  CAS  Google Scholar 

  • Kaushik, S., & Cuervo, A. M. (2006). Autophagy as a cell-repair mechanism: Activation of chaperone-mediated autophagy during oxidative stress. Molecular Aspects of Medicine, 27, 444–454. doi:10.1016/j.mam.2006.08.007.

    Article  PubMed  CAS  Google Scholar 

  • Keller, J. N., Gee, J., & Ding, Q. (2002). The proteasome in brain aging. Ageing Research Reviews, 1, 279–293. doi:10.1016/S1568-1637(01)00006-X.

    Article  PubMed  CAS  Google Scholar 

  • Klucken, J., Shin, Y., Masliah, E., Hyman, B. T., & McLean, P. J. (2004). Hsp70 reduces alpha-synuclein aggregation and toxicity. The Journal of Biological Chemistry, 279, 25497–25502. doi:10.1074/jbc.M400255200.

    Article  PubMed  CAS  Google Scholar 

  • Kotzbauer, P. T., Giasson, B. I., Kravitz, A. V., et al. (2004). Fibrillization of alpha-synuclein and tau in familial Parkinson’s disease caused by the A53T alpha-synuclein mutation. Experimental Neurology, 187, 279–288. doi:10.1016/j.expneurol.2004.01.007.

    Article  PubMed  CAS  Google Scholar 

  • Lantos, P. L. (1998). The definition of multiple system atrophy: A review of recent developments. Journal of Neuropathology and Experimental Neurology, 57, 1099–1111. doi:10.1097/00005072-199812000-00001.

    Article  PubMed  CAS  Google Scholar 

  • Lee, D. H., & Goldberg, A. L. (1998). Proteasome inhibitors: Valuable new tools for cell biologists. Trends in Cell Biology, 8, 397–403. doi:10.1016/S0962-8924(98)01346-4.

    Article  PubMed  CAS  Google Scholar 

  • Lee, H. J., Khoshaghideh, F., Patel, S., & Lee, S. J. (2004a). Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. The Journal of Neuroscience, 24, 1888–1896. doi:10.1523/JNEUROSCI.3809-03.2004.

    Article  PubMed  CAS  Google Scholar 

  • Lee, V. M., Giasson, B. I., & Trojanowski, J. (2004b). More than just two peas in a pod: Common amyloidogenic properties of tau and alpha-synuclein in neurodegenerative diseases. Trends in Neurosciences, 27, 129–134. doi:10.1016/j.tins.2004.01.007.

    Article  PubMed  CAS  Google Scholar 

  • Lee, H. J., & Lee, S. J. (2002). Characterization of cytoplasmic alpha-synuclein aggregates. Fibril formation is tightly linked to the inclusion-forming process in cells. The Journal of Biological Chemistry, 277, 48976–48983. doi:10.1074/jbc.M208192200.

    Article  PubMed  CAS  Google Scholar 

  • Massey, A. C., Zhang, C., & Cuervo, A. M. (2006). Chaperone-mediated autophagy in aging and disease. Current Topics in Developmental Biology, 73, 205–235. doi:10.1016/S0070-2153(05)73007-6.

    Article  PubMed  CAS  Google Scholar 

  • McLean, P. J., Kawamata, H., Shariff, S., et al. (2002). TorsinA and heat shock proteins act as molecular chaperones: Suppression of alpha-synuclein aggregation. Journal of Neurochemistry, 83, 846–854. doi:10.1046/j.1471-4159.2002.01190.x.

    Article  PubMed  CAS  Google Scholar 

  • McLean, P. J., Klucken, J., Shin, Y., & Hyman, B. T. (2004). Geldanamycin induces Hsp70 and prevents alpha-synuclein aggregation and toxicity in vitro. Biochemical and Biophysical Research Communications, 321, 665–669. doi:10.1016/j.bbrc.2004.07.021.

    Article  PubMed  CAS  Google Scholar 

  • Neuhoff, V., Philipp, K., Zimmer, H. G., & Mesecke, S. (1979). A simple, versatile, sensitive and volume-independent method for quantitative protein determination which is independent of other external influences. Hoppe-Seyler’s Zeitschrift fur Physiologische Chemie, 360, 1657–1670.

    PubMed  CAS  Google Scholar 

  • Norris, E. H., Giasson, B. I., Ischiropoulos, H., & Lee, V. M. (2003). Effects of oxidative and nitrative challenges on alpha-synuclein fibrillogenesis involve distinct mechanisms of protein modifications. The Journal of Biological Chemistry, 278, 27230–27240. doi:10.1074/jbc.M212436200.

    Article  PubMed  CAS  Google Scholar 

  • 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. The Journal of Neuroscience, 20, 6048–6054.

    PubMed  CAS  Google Scholar 

  • Rekas, A., Adda, C. G., Andrew Aquilina, J., et al. (2004). Interaction of the molecular chaperone alphaB-crystallin with alpha-synuclein: Effects on amyloid fibril formation and chaperone activity. Journal of Molecular Biology, 340, 1167–1183. doi:10.1016/j.jmb.2004.05.054.

    Article  PubMed  CAS  Google Scholar 

  • Richter-Landsberg, C., & Bauer, N. G. (2004). Tau-inclusion body formation in oligodendroglia: The role of stress proteins and proteasome inhibition. International Journal of Developmental Neuroscience, 22, 443–451. doi:10.1016/j.ijdevneu.2004.07.003.

    Article  PubMed  CAS  Google Scholar 

  • Richter-Landsberg, C., & Goldbaum, O. (2003). Stress proteins in neural cells: Functional roles in health and disease. Cellular and Molecular Life Sciences, 60, 337–349. doi:10.1007/s000180300028.

    Article  PubMed  CAS  Google Scholar 

  • Richter-Landsberg, C., & Heinrich, M. (1996). OLN-93: a new permanent oligodendroglia cell line derived from primary rat brain glial cultures. Journal of Neuroscience Research, 45, 161–173. doi:10.1002/(SICI)1097-4547(19960715)45:2<161::AID-JNR8>3.0.CO;2-8.

    Article  PubMed  CAS  Google Scholar 

  • Ross, C. A., & Poirier, M. A. (2005). Opinion: What is the role of protein aggregation in neurodegeneration? Nature Reviews. Molecular Cell Biology, 6, 891–898. doi:10.1038/nrm1742.

    Article  PubMed  CAS  Google Scholar 

  • Sherman, M. Y., & Goldberg, A. L. (2001). Cellular defenses against unfolded proteins: A cell biologist thinks about neurodegenerative diseases. Neuron, 29, 15–32. doi:10.1016/S0896-6273(01)00177-5.

    Article  PubMed  CAS  Google Scholar 

  • Shin, Y., Klucken, J., Patterson, C., Hyman, B. T., & McLean, P. J. (2005). The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways. The Journal of Biological Chemistry, 280, 23727–23734. doi:10.1074/jbc.M503326200.

    Article  PubMed  CAS  Google Scholar 

  • Stefanis, L., Larsen, K. E., Rideout, H. J., Sulzer, D., & 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. The Journal of Neuroscience, 21, 9549–9560.

    PubMed  CAS  Google Scholar 

  • Tanaka, Y., Engelender, S., Igarashi, S., et al. (2001). Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Human Molecular Genetics, 10, 919–926. doi:10.1093/hmg/10.9.919.

    Article  PubMed  CAS  Google Scholar 

  • Tofaris, G. K., Layfield, R., & Spillantini, M. G. (2001). Alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Letters, 509, 22–26. doi:10.1016/S0014-5793(01)03115-5.

    Article  PubMed  CAS  Google Scholar 

  • Towbin, H., Staehelin, T., & Gordon, J. (1979). Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: Procedure and some applications. Proceedings of the National Academy of Sciences of the United States of America, 76, 4350–4354. doi:10.1073/pnas.76.9.4350.

    Article  PubMed  CAS  Google Scholar 

  • Tu, P., Galvin, J., Giasson, B. I., et al. (1998). Glial cytoplasmic inclusions in white matter olidogendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Annals of Neurology, 44, 415–422. doi:10.1002/ana.410440324.

    Article  PubMed  CAS  Google Scholar 

  • Uryu, K., Richter-Landsberg, C., Welch, W., et al. (2006). Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies. American Journal of Pathology, 168, 947–961. doi:10.2353/ajpath.2006.050770.

    Article  PubMed  CAS  Google Scholar 

  • Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N., & Rubinsztein, D. C. (2003). Alpha-synuclein is degraded by both autophagy and the proteasome. The Journal of Biological Chemistry, 278, 25009–25013. doi:10.1074/jbc.M300227200.

    Article  PubMed  CAS  Google Scholar 

  • Zarranz, J. J., Alegre, J., Gómez-Esteban, J. C., et al. (2004). The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Annals of Neurology, 55, 164–173. doi:10.1002/ana.10795.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

This work was supported by the Deutsche Forschungsgemeinschaft, Germany and the Tönjes-Vagt Stiftung (Bremen, Germany). The authors are grateful to Drs. Virginia Lee and John Trojanowski for helpful discussions and ongoing support.

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  1. Department of Biology, Molecular Neurobiology, University of Oldenburg, 26111, Oldenburg, Germany

    Michael Riedel, Olaf Goldbaum & Christiane Richter-Landsberg

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  1. Michael Riedel
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  3. Christiane Richter-Landsberg
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Correspondence to Christiane Richter-Landsberg.

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Riedel, M., Goldbaum, O. & Richter-Landsberg, C. α-Synuclein Promotes the Recruitment of Tau to Protein Inclusions in Oligodendroglial Cells: Effects of Oxidative and Proteolytic Stress. J Mol Neurosci 39, 226–234 (2009). https://doi.org/10.1007/s12031-009-9190-y

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