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Oxidative Stress Promotes Uptake, Accumulation, and Oligomerization of Extracellular α-Synuclein in Oligodendrocytes

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Abstract

The accumulation and aggregation of α-synuclein (α-Syn) in glial cytoplasmic inclusions originating in oligodendrocytes is a characteristic hallmark of multiple system atrophy, a progressive adult onset neurodegenerative disorder. The origin of α-Syn deposition in oligodendrocytes in multiple system atrophy is still unclear, but the uptake of α-Syn from the environment after neuronal secretion has been discussed. The present study was undertaken to investigate the consequences of α-Syn uptake from the environment in cultured oligodendroglial cells and its localization and potential to form intracellular aggregates in the absence or presence of the microtubule-associated protein tau, which has been demonstrated to act synergistically with α-Syn. Primary rat brain oligodendrocytes and clonal oligodendroglial OLN-93 cells were incubated with human recombinant soluble and pre-aggregated α-Syn. The data show that oligodendrocytes are capable to take up and internalize soluble and pre-aggregated α-Syn from their growth medium. In a time-dependent manner, α-Syn oligomerizes and small intracellular aggregates are formed. These do not exert cytotoxic responses or mitochondrial impairment. Oxidative stress exerted by hydrogen peroxide further promotes α-Syn oligomer formation and leads to an enlargement of the aggregates. This process is not affected or modified by the presence of tau in OLN-93 cells. Furthermore, membrane lipid modification by docosahexaenoic acid promotes α-Syn uptake and oligomerization, indicating that changing the membrane lipid composition and structure contributes to the protein aggregation process and pathological events. Hence, although α-Syn taken up by oligodendrocytes from the environment is not toxic per se, under conditions of oxidative stress, which might occur during chronic disease progression and aging, aggregates are enlarged and eventually may contribute to cytotoxicity and cellular death.

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References

  • Angot E, Steiner JA, Hansen C, Li JY, Brundin P (2010) Are synucleinopathies prion-like disorders? Lancet Neurol 9:1128–1138

    Article  PubMed  Google Scholar 

  • Angot E, Steiner JA, Lema Tome CM et al. (2012) Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS One 7:e39465

    Google Scholar 

  • Assayag K, Yakunin E, Loeb V, Selkoe DJ, Sharon R (2007) Polyunsaturated fatty acids induce alpha-synuclein-related pathogenic changes in neuronal cells. Am J Pathol 171:2000–2011

    Article  CAS  PubMed  Google Scholar 

  • Badiola N, de Oliveira RM, Herrera F et al (2011) Tau enhances alpha-synuclein aggregation and toxicity in cellular models of synucleinopathy. PLoS One 6:e26609

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ben-Gedalya T, Loeb V, Israeli E, Altschuler Y, Selkoe DJ, Sharon R (2009) Alpha-synuclein and polyunsaturated fatty acids promote clathrin-mediated endocytosis and synaptic vesicle recycling. Traffic 10:218–234

    Google Scholar 

  • Borghi R, Marchese R, Negro A et al (2000) Full length alpha-synuclein is present in cerebrospinal fluid from Parkinson’s disease and normal subjects. Neurosci Lett 287:65–67

    Article  CAS  PubMed  Google Scholar 

  • Brand A, Bauer NG, Hallott A et al (2010) Membrane lipid modification by polyunsaturated fatty acids sensitizes oligodendroglial OLN-93 cells against oxidative stress and promotes up-regulation of heme oxygenase-1 (HSP32). J Neurochem 113:465–476

    Article  CAS  PubMed  Google Scholar 

  • Brand A, Gil S, Seger R, Yavin E (2001) Lipid constituents in oligodendroglial cells alter susceptibility to H2O2-induced apoptotic cell death via ERK activation. J Neurochem 76:910–918

    Article  CAS  PubMed  Google Scholar 

  • Cairns NJ, Atkinson PF, Hanger DP, Anderton BH, Daniel SE, Lantos PL (1997) Tau protein in the glial cytoplasmic inclusions of multiple system atrophy can be distinguished from abnormal tau in Alzheimer’s disease. Neurosci Lett 230:49–52

    Article  CAS  PubMed  Google Scholar 

  • Chin SS, Goldman JE (1996) Glial inclusions in CNS degenerative diseases. J Neuropathol Exp Neurol 55:499–508

    Article  CAS  PubMed  Google Scholar 

  • Choubey V, Safiulina D, Vaarmann A et al (2011) Mutant A53T alpha-synuclein induces neuronal death by increasing mitochondrial autophagy. J Biol Chem 286:10814–10824

    Article  CAS  PubMed  Google Scholar 

  • De Franceschi G, Frare E, Bubacco L, Mammi S, Fontana A, de Laureto PP (2009) Molecular insights into the interaction between alpha-synuclein and docosahexaenoic acid. J Mol Biol 394:94–107

    Article  PubMed  Google Scholar 

  • Desplats P, Lee HJ, Bae EJ et al (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A 106:13010–13015

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dohm CP, Kermer P, Bahr M (2008) Aggregopathy in neurodegenerative diseases: mechanisms and therapeutic implication. Neurodegener Dis 5:321–338

    Article  CAS  PubMed  Google Scholar 

  • Dyall SC, Michael-Titus AT (2008) Neurological benefits of omega-3 fatty acids. Neuromol Med 10:219–235

    Article  CAS  Google Scholar 

  • El-Agnaf OM, Salem SA, Paleologou KE et al (2003) Alpha-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB J 17:1945–1947

    CAS  PubMed  Google Scholar 

  • Emmanouilidou E, Elenis D, Papasilekas T et al (2011) Assessment of alpha-synuclein secretion in mouse and human brain parenchyma. PLoS One 6:e22225

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fellner L, Jellinger KA, Wenning GK, Stefanova N (2011) Glial dysfunction in the pathogenesis of alpha-synucleinopathies: emerging concepts. Acta Neuropathol 121:675–693

    Article  CAS  PubMed  Google Scholar 

  • Frost B, Diamond MI (2010) Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci 11:155–159

    CAS  PubMed Central  PubMed  Google Scholar 

  • Galpern WR, Lang AE (2006) Interface between tauopathies and synucleinopathies: a tale of two proteins. Ann Neurol 59:449–458

    Article  CAS  PubMed  Google Scholar 

  • Geddes JW (2005) alpha-Synuclein: a potent inducer of tau pathology. Exp Neurol 192:244–250

    Article  CAS  PubMed  Google Scholar 

  • Giasson BI, Forman MS, Higuchi M et al (2003) Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300:636–640

    Article  CAS  PubMed  Google Scholar 

  • Goedert M, Clavaguera F, Tolnay M (2010) The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci 33:317–325

    Article  CAS  PubMed  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. J Neurosci 23

  • Goldbaum O, Richter-Landsberg C (2004) Proteolytic stress causes heat shock protein induction, tau ubiquitination, and the recruitment of ubiquitin to tau-positive aggregates in oligodendrocytes in culture. J Neurosci 24

  • Hansen C, Angot E, Bergstrom AL et al (2011) Alpha-synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 121:715–725

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hsu LJ, Sagara Y, Arroyo A et al (2000) Alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol 157:401–410

    Article  CAS  PubMed  Google Scholar 

  • Jang A, Lee H-J, Suk J-E, Jung J-W, Kim K-P, Lee S-J (2010) Non-classical exocytosis of alpha-synuclein is sensitive to folding states and promoted under stress conditions. J Neurochem 113

  • Jellinger KA, Lantos PL (2010) Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: an update. Acta Neuropathol 119:657–667

    Article  CAS  PubMed  Google Scholar 

  • Kanda S, Bishop JF, Eglitis MA, Yang Y, Mouradian MM (2000) Enhanced vulnerability to oxidative stress by alpha-synuclein mutations and C-terminal truncation. Neuroscience 97:279–284

    Article  CAS  PubMed  Google Scholar 

  • Kisos H, Pukass K, Ben-Hur T, Richter-Landsberg C, Sharon R (2012) Increased neuronal alpha-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling alpha-synucleinopathies. PLoS One 7:e46817

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kragh CL, Lund LB, Febbraro F et al (2009) Alpha-Synuclein aggregation and Ser-129 phosphorylation-dependent cell death in oligodendroglial cells. J Biol Chem 284:10211–10222

    Article  CAS  PubMed  Google Scholar 

  • Lee HJ, Choi C, Lee SJ (2002) 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

    Article  CAS  PubMed  Google Scholar 

  • Lee HJ, Khoshaghideh F, Patel S, Lee SJ (2004a) Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci 24:1888–1896

    Article  CAS  PubMed  Google Scholar 

  • Lee HJ, Patel S, Lee SJ (2005) Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci 25:6016–6024

    Article  CAS  PubMed  Google Scholar 

  • Lee HJ, Suk JE, Bae EJ, Lee JH, Paik SR, Lee SJ (2008) Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. Int J Biochem Cell Biol 40:1835–1849

    Article  CAS  PubMed  Google Scholar 

  • Lee HJ, Suk JE, Patrick C et al (2010) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285:9262–9272

    Article  CAS  PubMed  Google Scholar 

  • Lee VM, Giasson BI, Trojanowski JQ (2004b) More than just two peas in a pod: common amyloidogenic properties of tau and alpha-synuclein in neurodegenerative diseases. Trends Neurosci 27:129–134

    Article  CAS  PubMed  Google Scholar 

  • Luk KC, Kehm VM, Zhang B, O’Brien P, Trojanowski JQ, Lee VM (2012) Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice. J Exp Med 209:975–986

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Luk KC, Song C, O’Brien P et al (2009) Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A 106:20051–20056

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Miller DW, Johnson JM, Solano SM, Hollingsworth ZR, Standaert DG, Young AB (2005) Absence of alpha-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia. J Neural Transm 112:1613–1624

    Article  CAS  PubMed  Google Scholar 

  • Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K (2002) Demonstration of alpha-synuclein immunoreactivity in neuronal and glial cytoplasm in normal human brain tissue using proteinase K and formic acid pretreatment. Exp Neurol 176:98–104

    Article  CAS  PubMed  Google Scholar 

  • Nakamura K, Nemani VM, Azarbal F et al (2011) Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J Biol Chem 286:20710–20726

    Article  CAS  PubMed  Google Scholar 

  • Neuhoff V., Philipp K, Zimmer HG, Mesecke S (1979) simple, versatile, sensitive and volume-independent method for quantitative protein determination which is independent of other external influences. Hoppe-Seylers Zeitschrift Fur Physiologische Chemie 360

  • Norris EH, Giasson BI, Ischiropoulos H, Lee VM (2003) Effects of oxidative and nitrative challenges on alpha-synuclein fibrillogenesis involve distinct mechanisms of protein modifications. J Biol Chem 278:27230–27240

    Article  CAS  PubMed  Google Scholar 

  • Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 20:6048–6054

    CAS  PubMed  Google Scholar 

  • Perrin RJ, Woods WS, Clayton DF, George JM (2001) Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins. J Biol Chem 276:41958–41962

    Article  CAS  PubMed  Google Scholar 

  • Richter-Landsberg C, Gorath M, Trojanowski JQ, Lee VM (2000) alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res 62:9–14

    Article  CAS  PubMed  Google Scholar 

  • Richter-Landsberg C, Heinrich M (1996) OLN-93: a new permanent oligodendroglia cell line derived from primary rat brain glial cultures. J Neurosci Res 45:161–173

    Article  CAS  PubMed  Google Scholar 

  • Riedel M, Goldbaum O, Richter-Landsberg C (2009) Alpha-synuclein promotes the recruitment of tau to protein inclusions in oligodendroglial cells: effects of oxidative and proteolytic stress. J Mol Neurosci 39:226–234

    Article  CAS  PubMed  Google Scholar 

  • Riedel M, Goldbaum O, Schwarz L, Schmitt S, Richter-Landsberg C (2010) 17-AAG induces cytoplasmic alpha-synuclein aggregate clearance by induction of autophagy. PLoS One 5:e8753

    Article  PubMed Central  PubMed  Google Scholar 

  • Riedel M, Goldbaum O, Wille M, Richter-Landsberg C (2011) Membrane lipid modification by docosahexaenoic acid (DHA) promotes the formation of alpha-synuclein inclusion bodies immunopositive for SUMO-1 in oligodendroglial cells after oxidative stress. J Mol Neurosci 43:290–302

    Article  CAS  PubMed  Google Scholar 

  • Ross CA, Poirier MA (2005) Opinion: what is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol 6:891–898

    Article  CAS  PubMed  Google Scholar 

  • Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ (2003a) The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson’s disease. Neuron 37:583–595

    Article  CAS  PubMed  Google Scholar 

  • Sharon R, Bar-Joseph I, Mirick GE, Serhan CN, Selkoe DJ (2003b) Altered fatty acid composition of dopaminergic neurons expressing alpha-synuclein and human brains with alpha-synucleinopathies. J Biol Chem 278:49874–49881

    Article  CAS  PubMed  Google Scholar 

  • Skovronsky DM, Lee VM, Trojanowski JQ (2006) Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol 1:151–170

    Article  CAS  PubMed  Google Scholar 

  • Stahnke T, Stadelmann C, Netzler A, Bruck W, Richter-Landsberg C (2007) Differential upregulation of heme oxygenase-1 (HSP32) in glial cells after oxidative stress and in demyelinating disorders. J Mol Neurosci 32:25–37

    Article  CAS  PubMed  Google Scholar 

  • Stefanova N, Klimaschewski L, Poewe W, Wenning GK, Reindl M (2001) Glial cell death induced by overexpression of alpha-synuclein. J Neurosci Res 65:432–438

    Article  CAS  PubMed  Google Scholar 

  • Stefanova N, Reindl M, Neumann M et al (2005) Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy. Am J Pathol 166:869–876

    Article  CAS  PubMed  Google Scholar 

  • Takeda A, Arai N, Komori T, Iseki E, Kato S, Oda M (1997) Tau immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 234:63–66

    Article  CAS  PubMed  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. Hum Mol Genet 10:919–926

    Article  CAS  PubMed  Google Scholar 

  • Tsuboi K, Grzesiak JJ, Bouvet M, Hashimoto M, Masliah E, Shults CW (2005) Alpha-synuclein overexpression in oligodendrocytic cells results in impaired adhesion to fibronectin and cell death. Mol Cell Neurosci 29:259–268

    Article  CAS  PubMed  Google Scholar 

  • Tu PH, Galvin JE, Baba M et al (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 44:415–422

    Article  CAS  PubMed  Google Scholar 

  • Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L (2008) Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem 283:23542–23556

    Article  CAS  PubMed  Google Scholar 

  • Wakabayashi K, Takahashi H (2006) Cellular pathology in multiple system atrophy. Neuropathology 26:338–345

    Article  PubMed  Google Scholar 

  • Waxman EA, Giasson BI (2011) Induction of intracellular tau aggregation is promoted by alpha-synuclein seeds and provides novel insights into the hyperphosphorylation of tau. J Neurosci 31:7604–7618

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278:25009–25013

    Article  CAS  PubMed  Google Scholar 

  • Wenning GK, Stefanova N, Jellinger KA, Poewe W, Schlossmacher MG (2008) Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 64:239–246

    Article  CAS  PubMed  Google Scholar 

  • Yakunin E, Loeb V, Kisos H et al (2012) Alpha-synuclein neuropathology is controlled by nuclear hormone receptors and enhanced by docosahexaenoic acid in a mouse model for Parkinson’s disease. Brain Pathol 22:280–294

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors thank Dr. Poul Henning Jensen, Aarhus University, Denmark, for the generous gift of human recombinant α-Syn. We thank Angelika Spanjer and Irina Fomins for expert technical help and Dr. Olaf Goldbaum for helpful discussions.

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

    Katharina Pukaß & Christiane Richter-Landsberg

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  1. Katharina Pukaß
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Correspondence to Christiane Richter-Landsberg.

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Pukaß, K., Richter-Landsberg, C. Oxidative Stress Promotes Uptake, Accumulation, and Oligomerization of Extracellular α-Synuclein in Oligodendrocytes. J Mol Neurosci 52, 339–352 (2014). https://doi.org/10.1007/s12031-013-0154-x

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