Acta Neuropathologica

, 121:675 | Cite as

Glial dysfunction in the pathogenesis of α-synucleinopathies: emerging concepts

  • Lisa Fellner
  • Kurt A. Jellinger
  • Gregor K. Wenning
  • Nadia Stefanova


Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are adult onset neurodegenerative disorders characterised by prominent intracellular α-synuclein aggregates (α-synucleinopathies). The glial contribution to neurodegeneration in α-synucleinopathies was largely underestimated until recently. However, brains of PD and DLB patients exhibit not only neuronal inclusions such as Lewy bodies or Lewy neurites but also glial α-synuclein aggregates. Accumulating experimental evidence in PD models suggests that astrogliosis and microgliosis act as important mediators of neurodegeneration playing a pivotal role in both disease initiation and progression. In MSA, oligodendrocytes are intriguingly affected by aberrant cytoplasmic accumulation of α-synuclein (glial cytoplasmic inclusions, Papp-Lantos bodies). Converging evidence from human postmortem studies and transgenic MSA models suggests that oligodendroglial dysfunction both triggers and exacerbates neuronal degeneration. This review summarises the wide range of responsibilities of astroglia, microglia and oligodendroglia in the healthy brain and the changes in glial function associated with ageing. We then provide a critical analysis of the role of glia in α-synucleinopathies including putative mechanisms promoting a chronically diseased glial microenvironment which can lead to detrimental neuronal changes, including cell loss. Finally, major therapeutic strategies targeting glial pathology in α-synucleinopathies as well as current pitfalls for disease-modification in clinical trials are discussed.


α-Synuclein Microglia Astroglia Oligodendroglia Neurodegeneration Parkinson’s disease Multiple system atrophy 


  1. 1.
    Abeliovich A, Schmitz Y, Farinas I et al (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252PubMedCrossRefGoogle Scholar
  2. 2.
    Akira S (2001) Toll-like receptors and innate immunity. Adv Immunol 78:1–56PubMedCrossRefGoogle Scholar
  3. 3.
    Al-Chalabi A, Durr A, Wood NW et al (2009) Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy. PLoS One 4:e7114PubMedCrossRefGoogle Scholar
  4. 4.
    Albert M (1993) Neuropsychological and neurophysiological changes in healthy adult humans across the age range. Neurobiol Aging 14:623–625PubMedCrossRefGoogle Scholar
  5. 5.
    Amiry-Moghaddam M, Otsuka T, Hurn PD et al (2003) An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc Natl Acad Sci USA 100:2106–2111PubMedCrossRefGoogle Scholar
  6. 6.
    Anderson JP, Walker DE, Goldstein JM et al (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281:29739–29752PubMedCrossRefGoogle Scholar
  7. 7.
    Appel K, Honegger P, Gebicke-Haerter PJ (1995) Expression of interleukin-3 and tumor necrosis factor-beta mRNAs in cultured microglia. J Neuroimmunol 60:83–91PubMedCrossRefGoogle Scholar
  8. 8.
    Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22:208–215PubMedCrossRefGoogle Scholar
  9. 9.
    Aubin N, Curet O, Deffois A, Carter C (1998) Aspirin and salicylate protect against MPTP-induced dopamine depletion in mice. J Neurochem 71:1635–1642PubMedCrossRefGoogle Scholar
  10. 10.
    Austin SA, Floden AM, Murphy EJ, Combs CK (2006) Alpha-synuclein expression modulates microglial activation phenotype. J Neurosci 26:10558–10563PubMedCrossRefGoogle Scholar
  11. 11.
    Baba M, Nakajo S, Tu PH et al (1998) Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152:879–884PubMedGoogle Scholar
  12. 12.
    Balasingam V, Dickson K, Brade A, Yong VW (1996) Astrocyte reactivity in neonatal mice: apparent dependence on the presence of reactive microglia/macrophages. Glia 18:11–26PubMedCrossRefGoogle Scholar
  13. 13.
    Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81:871–927PubMedGoogle Scholar
  14. 14.
    Becker C, Jick SS, Meier CR (2011) NSAID use and risk of Parkinson disease: a population-based case-control study. Eur J Neurol. doi:10.1111/j.1468-1331.2011.03399.x
  15. 15.
    Benner EJ, Banerjee R, Reynolds AD et al (2008) Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 3:e1376PubMedCrossRefGoogle Scholar
  16. 16.
    Benner EJ, Mosley RL, Destache CJ et al (2004) Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 101:9435–9440PubMedCrossRefGoogle Scholar
  17. 17.
    Beyer K, Ariza A (2007) Protein aggregation mechanisms in synucleinopathies: commonalities and differences. J Neuropathol Exp Neurol 66:965–974PubMedCrossRefGoogle Scholar
  18. 18.
    Bianco F, Pravettoni E, Colombo A et al (2005) Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. J Immunol 174:7268–7277PubMedGoogle Scholar
  19. 19.
    Biju K, Zhou Q, Li G et al (2010) Macrophage-mediated GDNF delivery protects against dopaminergic neurodegeneration: a therapeutic strategy for Parkinson’s disease. Mol Ther 18:1536–1544PubMedCrossRefGoogle Scholar
  20. 20.
    Braak H, Del Tredici K (2004) Poor and protracted myelination as a contributory factor to neurodegenerative disorders. Neurobiol Aging 25:19–23PubMedCrossRefGoogle Scholar
  21. 21.
    Braak H, Del Tredici K (2009) Neuroanatomy and pathology of sporadic Parkinson’s disease. Adv Anat Embryol Cell Biol 201:1–119PubMedGoogle Scholar
  22. 22.
    Braak H, Del Tredici K, Bratzke H, Hamm-Clement J, Sandmann-Keil D, Rub U (2002) Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson’s disease (preclinical and clinical stages). J Neurol 249(Suppl 3):III/1–III/5Google Scholar
  23. 23.
    Braak H, Rub U, Gai WP, Del Tredici K (2003) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110:517–536PubMedCrossRefGoogle Scholar
  24. 24.
    Braak H, Sastre M, Del Tredici K (2007) Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease. Acta Neuropathol 114:231–241PubMedCrossRefGoogle Scholar
  25. 25.
    Bradl M, Lassmann H (2010) Oligodendrocytes: biology and pathology. Acta Neuropathol 119:37–53PubMedCrossRefGoogle Scholar
  26. 26.
    Breidert T, Callebert J, Heneka MT, Landreth G, Launay JM, Hirsch EC (2002) Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson’s disease. J Neurochem 82:615–624PubMedCrossRefGoogle Scholar
  27. 27.
    Brochard V, Combadiere B, Prigent A et al (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119:182–192PubMedGoogle Scholar
  28. 28.
    Bundesen LQ, Scheel TA, Bregman BS, Kromer LF (2003) Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats. J Neurosci 23:7789–7800PubMedGoogle Scholar
  29. 29.
    Bunge RP (1968) Glial cells and the central myelin sheath. Physiol Rev 48:197–251PubMedGoogle Scholar
  30. 30.
    Burke RE, Dauer WT, Vonsattel JP (2008) A critical evaluation of the Braak staging scheme for Parkinson’s disease. Ann Neurol 64:485–491PubMedCrossRefGoogle Scholar
  31. 31.
    Bush TG, Puvanachandra N, Horner CH et al (1999) Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23:297–308PubMedCrossRefGoogle Scholar
  32. 32.
    Bushong EA, Martone ME, Ellisman MH (2004) Maturation of astrocyte morphology and the establishment of astrocyte domains during postnatal hippocampal development. Int J Dev Neurosci 22:73–86PubMedCrossRefGoogle Scholar
  33. 33.
    Butt AM, Ibrahim M, Berry M (1998) Axon-myelin sheath relations of oligodendrocyte unit phenotypes in the adult rat anterior medullary velum. J Neurocytol 27:259–269PubMedGoogle Scholar
  34. 34.
    Buttini M, Boddeke H (1995) Peripheral lipopolysaccharide stimulation induces interleukin-1 beta messenger RNA in rat brain microglial cells. Neuroscience 65:523–530PubMedCrossRefGoogle Scholar
  35. 35.
    Calne DB, Mizuno Y (2004) The neuromythology of Parkinson’s disease. Parkinsonism Relat Disord 10:319–322PubMedCrossRefGoogle Scholar
  36. 36.
    Campbell BC, McLean CA, Culvenor JG et al (2001) The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson’s disease. J Neurochem 76:87–96PubMedCrossRefGoogle Scholar
  37. 37.
    Carmignoto G, Gomez-Gonzalo M (2010) The contribution of astrocyte signalling to neurovascular coupling. Brain Res Rev 63:138–148PubMedCrossRefGoogle Scholar
  38. 38.
    Casarejos MJ, Menendez J, Solano RM, Rodriguez-Navarro JA, Garcia de Yebenes J, Mena MA (2006) Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline. J Neurochem 97:934–946PubMedCrossRefGoogle Scholar
  39. 39.
    Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC (2005) Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123:383–396PubMedCrossRefGoogle Scholar
  40. 40.
    Choi DK, Pennathur S, Perier C et al (2005) Ablation of the inflammatory enzyme myeloperoxidase mitigates features of Parkinson’s disease in mice. J Neurosci 25:6594–6600PubMedCrossRefGoogle Scholar
  41. 41.
    Ciccarelli R, Ballerini P, Sabatino G et al (2001) Involvement of astrocytes in purine-mediated reparative processes in the brain. Int J Dev Neurosci 19:395–414PubMedCrossRefGoogle Scholar
  42. 42.
    Conde JR, Streit WJ (2006) Microglia in the aging brain. J Neuropathol Exp Neurol 65:199–203PubMedGoogle Scholar
  43. 43.
    Croisier E, Graeber MB (2006) Glial degeneration and reactive gliosis in alpha-synucleinopathies: the emerging concept of primary gliodegeneration. Acta Neuropathol 112:517–530PubMedCrossRefGoogle Scholar
  44. 44.
    de Silva HR, Khan NL, Wood NW (2000) The genetics of Parkinson’s disease. Curr Opin Genet Dev 10:292–298PubMedCrossRefGoogle Scholar
  45. 45.
    Dean JM, Wang X, Kaindl AM et al (2010) Microglial MyD88 signaling regulates acute neuronal toxicity of LPS-stimulated microglia in vitro. Brain Behav Immun 24:776–783PubMedCrossRefGoogle Scholar
  46. 46.
    Dehmer T, Heneka MT, Sastre M, Dichgans J, Schulz JB (2004) Protection by pioglitazone in the MPTP model of Parkinson’s disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J Neurochem 88:494–501PubMedCrossRefGoogle Scholar
  47. 47.
    del Rio-Hortega P (1932) Microglia. In: Penfield W (ed) Cytology and cellular pathology of the nervous system. Hoeber PB, New York, pp 483–534Google Scholar
  48. 48.
    Dermietzel R, Gao Y, Scemes E et al (2000) Connexin43 null mice reveal that astrocytes express multiple connexins. Brain Res Brain Res Rev 32:45–56PubMedCrossRefGoogle Scholar
  49. 49.
    Deshpande M, Zheng J, Borgmann K et al (2005) Role of activated astrocytes in neuronal damage: potential links to HIV-1-associated dementia. Neurotox Res 7:183–192PubMedCrossRefGoogle Scholar
  50. 50.
    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 USA 106:13010–13015PubMedCrossRefGoogle Scholar
  51. 51.
    Dickson DW, Lin W, Liu WK, Yen SH (1999) Multiple system atrophy: a sporadic synucleinopathy. Brain Pathol 9:721–732PubMedCrossRefGoogle Scholar
  52. 52.
    Dodel R, Spottke A, Gerhard A et al (2010) Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [(11)C] (R)-PK11195 PET (MEMSA-trial). Mov Disord 25:97–107PubMedGoogle Scholar
  53. 53.
    Domercq M, Sanchez-Gomez MV, Sherwin C, Etxebarria E, Fern R, Matute C (2007) System xc- and glutamate transporter inhibition mediates microglial toxicity to oligodendrocytes. J Immunol 178:6549–6556PubMedGoogle Scholar
  54. 54.
    Dorsey ER, Constantinescu R, Thompson JP et al (2007) Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68:384–386PubMedCrossRefGoogle Scholar
  55. 55.
    Durrenberger PF, Filiou MD, Moran LB et al (2009) DnaJB6 is present in the core of Lewy bodies and is highly up-regulated in parkinsonian astrocytes. J Neurosci Res 87:238–245PubMedCrossRefGoogle Scholar
  56. 56.
    Edwards TL, Scott WK, Almonte C et al (2010) Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 74:97–109PubMedCrossRefGoogle Scholar
  57. 57.
    Eklind S, Hagberg H, Wang X et al (2006) Effect of lipopolysaccharide on global gene expression in the immature rat brain. Pediatr Res 60:161–168PubMedCrossRefGoogle Scholar
  58. 58.
    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 17:1945–1947PubMedGoogle Scholar
  59. 59.
    Elbaz A, Ross OA, Ioannidis JP et al (2010) Independent and joint effects of the MAPT and SNCA genes in Parkinson disease. Ann Neurol 69:778–792CrossRefGoogle Scholar
  60. 60.
    Emmanouilidou E, Melachroinou K, Roumeliotis T et al (2010) Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 30:6838–6851PubMedCrossRefGoogle Scholar
  61. 61.
    Escartin C, Bonvento G (2008) Targeted activation of astrocytes: a potential neuroprotective strategy. Mol Neurobiol 38:231–241PubMedCrossRefGoogle Scholar
  62. 62.
    Esposito E, Di Matteo V, Benigno A, Pierucci M, Crescimanno G, Di Giovanni G (2007) Non-steroidal anti-inflammatory drugs in Parkinson’s disease. Exp Neurol 205:295–312PubMedCrossRefGoogle Scholar
  63. 63.
    Faissner A, Pyka M, Geissler M et al (2010) Contributions of astrocytes to synapse formation and maturation—potential functions of the perisynaptic extracellular matrix. Brain Res Rev 63:26–38PubMedCrossRefGoogle Scholar
  64. 64.
    Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114(Pt 5):2283–2301PubMedCrossRefGoogle Scholar
  65. 65.
    Flanary BE, Streit WJ (2003) Telomeres shorten with age in rat cerebellum and cortex in vivo. J Anti Aging Med 6:299–308PubMedCrossRefGoogle Scholar
  66. 66.
    Flanary BE, Streit WJ (2004) Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes. Glia 45:75–88PubMedCrossRefGoogle Scholar
  67. 67.
    Gagne JJ, Power MC (2010) Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology 74:995–1002PubMedCrossRefGoogle Scholar
  68. 68.
    Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VM (2008) Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci 28:7687–7698PubMedCrossRefGoogle Scholar
  69. 69.
    Gao HM, Zhou H, Zhang F, Wilson BC, Kam W, Hong JS (2011) HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration. J Neurosci 31:1081–1092PubMedCrossRefGoogle Scholar
  70. 70.
    Garcia-Matas S, Gutierrez-Cuesta J, Coto-Montes A et al (2008) Dysfunction of astrocytes in senescence-accelerated mice SAMP8 reduces their neuroprotective capacity. Aging Cell 7:630–640PubMedCrossRefGoogle Scholar
  71. 71.
    Gerhard A, Banati RB, Goerres GB et al (2003) [11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy. Neurology 61:686–689PubMedGoogle Scholar
  72. 72.
    Gerhard A, Pavese N, Hotton G et al (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 21:404–412PubMedCrossRefGoogle Scholar
  73. 73.
    Geser F, Jellinger KA, Köllensperger M, Stefanova N, Wenning GK (2010) Multiple system atrophy. Etiology, pathology, and pathogenesis. In: Schapira AHV, Lang AET, Fahn S (eds) Movement disorders 4. Elsevier, Saunders, pp 321–339CrossRefGoogle Scholar
  74. 74.
    Giasson BI, Duda JE, Murray IV et al (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985–989PubMedCrossRefGoogle Scholar
  75. 75.
    Gilman S, Low PA, Quinn N et al (1999) Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 163:94–98PubMedCrossRefGoogle Scholar
  76. 76.
    Ginhoux F, Greter M, Leboeuf M et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845PubMedCrossRefGoogle Scholar
  77. 77.
    Glanzer JG, Enose Y, Wang T et al (2007) Genomic and proteomic microglial profiling: pathways for neuroprotective inflammatory responses following nerve fragment clearance and activation. J Neurochem 102:627–645PubMedCrossRefGoogle Scholar
  78. 78.
    Golgi C (1903) Opera Omnia. Hoepli, MilanoGoogle Scholar
  79. 79.
    Gonzalez-Perez O, Alvarez-Buylla A (2011) Oligodendrogenesis in the subventricular zone and the role of epidermal growth factor. Brain Res RevGoogle Scholar
  80. 80.
    Graeber MB, Streit WJ (2010) Microglia: biology and pathology. Acta Neuropathol 119:89–105PubMedCrossRefGoogle Scholar
  81. 81.
    Greten-Harrison B, Polydoro M, Morimoto-Tomita M et al (2010) alphabetagamma-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction. Proc Natl Acad Sci USA 107:19573–19578PubMedCrossRefGoogle Scholar
  82. 82.
    Gu XL, Long CX, Sun L, Xie C, Lin X, Cai H (2010) Astrocytic expression of Parkinson’s disease-related A53T alpha-synuclein causes neurodegeneration in mice. Mol Brain 3:12PubMedCrossRefGoogle Scholar
  83. 83.
    Halassa MM, Fellin T, Takano H, Dong JH, Haydon PG (2007) Synaptic islands defined by the territory of a single astrocyte. J Neurosci 27:6473–6477PubMedCrossRefGoogle Scholar
  84. 84.
    Halliday GM, Stevens CH (2011) Glia: initiators and progressors of pathology in Parkinson’s disease. Mov Disord 26:6–17PubMedCrossRefGoogle Scholar
  85. 85.
    Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40:140–155PubMedCrossRefGoogle Scholar
  86. 86.
    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 121:715–725PubMedCrossRefGoogle Scholar
  87. 87.
    Hasegawa-Ishii S, Takei S, Inaba M et al (2010) Defects in cytokine-mediated neuroprotective glial responses to excitotoxic hippocampal injury in senescence-accelerated mouse. Brain Behav Immun 25:83–100PubMedCrossRefGoogle Scholar
  88. 88.
    Hashioka S, Klegeris A, Schwab C, McGeer PL (2009) Interferon-gamma-dependent cytotoxic activation of human astrocytes and astrocytoma cells. Neurobiol Aging 30:1924–1935PubMedCrossRefGoogle Scholar
  89. 89.
    Hayakawa N, Kato H, Araki T (2007) Age-related changes of astorocytes, oligodendrocytes and microglia in the mouse hippocampal CA1 sector. Mech Ageing Dev 128:311–316PubMedCrossRefGoogle Scholar
  90. 90.
    Hayes GM, Woodroofe MN, Cuzner ML (1987) Microglia are the major cell type expressing MHC class II in human white matter. J Neurol Sci 80:25–37PubMedCrossRefGoogle Scholar
  91. 91.
    Heneka MT, Rodriguez JJ, Verkhratsky A (2010) Neuroglia in neurodegeneration. Brain Res Rev 63:189–211PubMedCrossRefGoogle Scholar
  92. 92.
    Herrmann JE, Imura T, Song B et al (2008) STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci 28:7231–7243PubMedCrossRefGoogle Scholar
  93. 93.
    Hines DJ, Hines RM, Mulligan SJ, Macvicar BA (2009) Microglia processes block the spread of damage in the brain and require functional chloride channels. Glia 57:1610–1618PubMedCrossRefGoogle Scholar
  94. 94.
    Hirohata M, Ono K, Morinaga A, Yamada M (2008) Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. Neuropharmacology 54:620–627PubMedCrossRefGoogle Scholar
  95. 95.
    Hirsch EC, Hunot S, Hartmann A (2005) Neuroinflammatory processes in Parkinson’s disease. Parkinsonism Relat Disord 11(Suppl 1):S9–S15PubMedCrossRefGoogle Scholar
  96. 96.
    Hirschfeld M, Ma Y, Weis JH, Vogel SN, Weis JJ (2000) Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. J Immunol 165:618–622PubMedGoogle Scholar
  97. 97.
    Hlavanda E, Klement E, Kokai E et al (2007) Phosphorylation blocks the activity of tubulin polymerization-promoting protein (TPPP): identification of sites targeted by different kinases. J Biol Chem 282:29531–29539PubMedCrossRefGoogle Scholar
  98. 98.
    Hunter RL, Dragicevic N, Seifert K et al (2007) Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem 100:1375–1386PubMedCrossRefGoogle Scholar
  99. 99.
    Ikeda K, Akiyama H, Kondo H et al (1995) Thorn-shaped astrocytes: possibly secondarily induced tau-positive glial fibrillary tangles. Acta Neuropathol 90:620–625PubMedCrossRefGoogle Scholar
  100. 100.
    Ishizawa K, Komori T, Sasaki S, Arai N, Mizutani T, Hirose T (2004) Microglial activation parallels system degeneration in multiple system atrophy. J Neuropathol Exp Neurol 63:43–52PubMedGoogle Scholar
  101. 101.
    Iwai A, Masliah E, Yoshimoto M et al (1995) The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14:467–475PubMedCrossRefGoogle Scholar
  102. 102.
    Jakel RJ, Townsend JA, Kraft AD, Johnson JA (2007) Nrf2-mediated protection against 6-hydroxydopamine. Brain Res 1144:192–201PubMedCrossRefGoogle Scholar
  103. 103.
    Jander S, Pohl J, D’Urso D, Gillen C, Stoll G (1998) Time course and cellular localization of interleukin-10 mRNA and protein expression in autoimmune inflammation of the rat central nervous system. Am J Pathol 152:975–982PubMedGoogle Scholar
  104. 104.
    Jellinger KA (2003) Neuropathological spectrum of synucleinopathies. Mov Disord 18(Suppl 6):S2–S12PubMedCrossRefGoogle Scholar
  105. 105.
    Jellinger KA (2007) Lewy body disorders. In: Youdim MBH, Riederer P, Mandel SA, Battistin L, Lajtha A (eds) Degenerative diseases of the nervous system. Springer, New York, pp 267–343Google Scholar
  106. 106.
    Jellinger KA (2009) A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders. Biochim Biophys Acta 1792:730–740PubMedGoogle Scholar
  107. 107.
    Jellinger KA, Lantos PL (2010) Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: an update. Acta Neuropathol 119:657–667PubMedCrossRefGoogle Scholar
  108. 108.
    Jellinger KA, Seppi K, Wenning GK (2005) Grading of neuropathology in multiple system atrophy: proposal for a novel scale. Mov Disord 20(Suppl 12):S29–S36PubMedCrossRefGoogle Scholar
  109. 109.
    Jurewicz A, Matysiak M, Tybor K, Kilianek L, Raine CS, Selmaj K (2005) Tumour necrosis factor-induced death of adult human oligodendrocytes is mediated by apoptosis inducing factor. Brain 128:2675–2688PubMedCrossRefGoogle Scholar
  110. 110.
    Juurlink BH (1997) Response of glial cells to ischemia: roles of reactive oxygen species and glutathione. Neurosci Biobehav Rev 21:151–166PubMedCrossRefGoogle Scholar
  111. 111.
    Kahle PJ, Neumann M, Ozmen L et al (2002) Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 3:583–588PubMedCrossRefGoogle Scholar
  112. 112.
    Kandel ER (1991) Nerve cell and behavior. Principles of neural science. Elsevier, New York, pp 18–32Google Scholar
  113. 113.
    Kiefer R, Schweitzer T, Jung S, Toyka KV, Hartung HP (1998) Sequential expression of transforming growth factor-beta1 by T-cells, macrophages, and microglia in rat spinal cord during autoimmune inflammation. J Neuropathol Exp Neurol 57:385–395PubMedCrossRefGoogle Scholar
  114. 114.
    Klegeris A, Giasson BI, Zhang H, Maguire J, Pelech S, McGeer PL (2006) Alpha-synuclein and its disease-causing mutants induce ICAM-1 and IL-6 in human astrocytes and astrocytoma cells. FASEB J 20:2000–2008PubMedCrossRefGoogle Scholar
  115. 115.
    Klegeris A, Pelech S, Giasson BI et al (2008) Alpha-synuclein activates stress signaling protein kinases in THP-1 cells and microglia. Neurobiol Aging 29:739–752PubMedCrossRefGoogle Scholar
  116. 116.
    Knott C, Stern G, Kingsbury A, Welcher AA, Wilkin GP (2002) Elevated glial brain-derived neurotrophic factor in Parkinson’s diseased nigra. Parkinsonism Relat Disord 8:329–341PubMedCrossRefGoogle Scholar
  117. 117.
    Knox CA, Kokmen E, Dyck PJ (1989) Morphometric alteration of rat myelinated fibers with aging. J Neuropathol Exp Neurol 48:119–139PubMedCrossRefGoogle Scholar
  118. 118.
    Koehler RC, Roman RJ, Harder DR (2009) Astrocytes and the regulation of cerebral blood flow. Trends Neurosci 32:160–169PubMedCrossRefGoogle Scholar
  119. 119.
    Kofuji P, Newman EA (2004) Potassium buffering in the central nervous system. Neuroscience 129:1045–1056PubMedCrossRefGoogle Scholar
  120. 120.
    Kong LY, McMillian MK, Hudson PM, Jin L, Hong JS (1997) Inhibition of lipopolysaccharide-induced nitric oxide and cytokine production by ultralow concentrations of dynorphins in mixed glia cultures. J Pharmacol Exp Ther 280:61–66PubMedGoogle Scholar
  121. 121.
    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 284:10211–10222PubMedCrossRefGoogle Scholar
  122. 122.
    Lasn H, Winblad B, Bogdanovic N (2006) Neuroglia in the inferior olivary nucleus during normal aging and Alzheimer’s disease. J Cell Mol Med 10:145–156PubMedCrossRefGoogle Scholar
  123. 123.
    Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170PubMedCrossRefGoogle Scholar
  124. 124.
    Lee HJ, Patel S, Lee SJ (2005) Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci 25:6016–6024PubMedCrossRefGoogle Scholar
  125. 125.
    Lee HJ, Suk JE, Bae EJ, Lee SJ (2008) Clearance and deposition of extracellular alpha-synuclein aggregates in microglia. Biochem Biophys Res Commun 372:423–428PubMedCrossRefGoogle Scholar
  126. 126.
    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 285:9262–9272PubMedCrossRefGoogle Scholar
  127. 127.
    Letiembre M, Liu Y, Walter S et al (2009) Screening of innate immune receptors in neurodegenerative diseases: a similar pattern. Neurobiol Aging 30:759–768PubMedCrossRefGoogle Scholar
  128. 128.
    Liberto CM, Albrecht PJ, Herx LM, Yong VW, Levison SW (2004) Pro-regenerative properties of cytokine-activated astrocytes. J Neurochem 89:1092–1100PubMedCrossRefGoogle Scholar
  129. 129.
    Liddell JR, Robinson SR, Dringen R, Bishop GM (2010) Astrocytes retain their antioxidant capacity into advanced old age. Glia 58:1500–1509PubMedGoogle Scholar
  130. 130.
    Lien E, Means TK, Heine H et al (2000) Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide. J Clin Invest 105:497–504PubMedCrossRefGoogle Scholar
  131. 131.
    Lindersson E, Lundvig D, Petersen C et al (2005) p25alpha Stimulates alpha-synuclein aggregation and is co-localized with aggregated alpha-synuclein in alpha-synucleinopathies. J Biol Chem 280:5703–5715PubMedCrossRefGoogle Scholar
  132. 132.
    Liu JS, Amaral TD, Brosnan CF, Lee SC (1998) IFNs are critical regulators of IL-1 receptor antagonist and IL-1 expression in human microglia. J Immunol 161:1989–1996PubMedGoogle Scholar
  133. 133.
    Long-Smith CM, Collins L, Toulouse A, Sullivan AM, Nolan YM (2010) Interleukin-1beta contributes to dopaminergic neuronal death induced by lipopolysaccharide-stimulated rat glia in vitro. J Neuroimmunol 226:20–26PubMedCrossRefGoogle Scholar
  134. 134.
    Lu L, Mak YT, Fang M, Yew DT (2009) The difference in gliosis induced by beta-amyloid and Tau treatments in astrocyte cultures derived from senescence accelerated and normal mouse strains. Biogerontology 10:695–710PubMedCrossRefGoogle Scholar
  135. 135.
    Lu X, Bing G, Hagg T (2000) Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats. Neuroscience 97:285–291PubMedCrossRefGoogle Scholar
  136. 136.
    Lynch MA (2009) The multifaceted profile of activated microglia. Mol Neurobiol 40:139–156PubMedCrossRefGoogle Scholar
  137. 137.
    Mackenzie IR (2000) Activated microglia in dementia with Lewy bodies. Neurology 55:132–134PubMedGoogle Scholar
  138. 138.
    Maehlen J, Olsson T, Zachau A, Klareskog L, Kristensson K (1989) Local enhancement of major histocompatibility complex (MHC) class I and II expression and cell infiltration in experimental allergic encephalomyelitis around axotomized motor neurons. J Neuroimmunol 23:125–132PubMedCrossRefGoogle Scholar
  139. 139.
    Marks WJ Jr, Bartus RT, Siffert J et al (2010) Gene delivery of AAV2-neurturin for Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol 9:1164–1172PubMedCrossRefGoogle Scholar
  140. 140.
    Marner L, Nyengaard JR, Tang Y, Pakkenberg B (2003) Marked loss of myelinated nerve fibers in the human brain with age. J Comp Neurol 462:144–152PubMedCrossRefGoogle Scholar
  141. 141.
    Masliah E, Rockenstein E, Adame A et al (2005) Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. Neuron 46:857–868PubMedCrossRefGoogle Scholar
  142. 142.
    Matsuo A, Akiguchi I, Lee GC, McGeer EG, McGeer PL, Kimura J (1998) Myelin degeneration in multiple system atrophy detected by unique antibodies. Am J Pathol 153:735–744PubMedCrossRefGoogle Scholar
  143. 143.
    Matute C, Alberdi E, Domercq M et al (2007) Excitotoxic damage to white matter. J Anat 210:693–702PubMedCrossRefGoogle Scholar
  144. 144.
    McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291PubMedGoogle Scholar
  145. 145.
    McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Disord 23:474–483PubMedCrossRefGoogle Scholar
  146. 146.
    McKeith IG, Burn DJ, Ballard CG et al (2003) Dementia with Lewy bodies. Semin Clin Neuropsychiatry 8:46–57PubMedCrossRefGoogle Scholar
  147. 147.
    McKeith IG, Galasko D, Kosaka K et al (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47:1113–1124PubMedGoogle Scholar
  148. 148.
    McTigue DM, Tripathi RB (2008) The life, death, and replacement of oligodendrocytes in the adult CNS. J Neurochem 107:1–19PubMedCrossRefGoogle Scholar
  149. 149.
    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 112:1613–1624PubMedCrossRefGoogle Scholar
  150. 150.
    Mirza B, Hadberg H, Thomsen P, Moos T (2000) The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson’s disease. Neuroscience 95:425–432PubMedCrossRefGoogle Scholar
  151. 151.
    Mizuno T, Kuno R, Nitta A et al (2005) Protective effects of nicergoline against neuronal cell death induced by activated microglia and astrocytes. Brain Res 1066:78–85PubMedCrossRefGoogle Scholar
  152. 152.
    Mollenhauer B, Locascio JJ, Schulz-Schaeffer W, Sixel-Doring F, Trenkwalder C, Schlossmacher MG (2011) alpha-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. Lancet Neurol 10:230–240PubMedCrossRefGoogle Scholar
  153. 153.
    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 176:98–104PubMedCrossRefGoogle Scholar
  154. 154.
    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 ChemGoogle Scholar
  155. 155.
    Nave KA, Trapp BD (2008) Axon-glial signaling and the glial support of axon function. Annu Rev Neurosci 31:535–561PubMedCrossRefGoogle Scholar
  156. 156.
    Neumann H, Schweigreiter R, Yamashita T, Rosenkranz K, Wekerle H, Barde YA (2002) Tumor necrosis factor inhibits neurite outgrowth and branching of hippocampal neurons by a rho-dependent mechanism. J Neurosci 22:854–862PubMedGoogle Scholar
  157. 157.
    Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318PubMedCrossRefGoogle Scholar
  158. 158.
    Nishie M, Mori F, Fujiwara H et al (2004) Accumulation of phosphorylated alpha-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy. Acta Neuropathol 107:292–298PubMedCrossRefGoogle Scholar
  159. 159.
    Nishioka K, Hayashi S, Farrer MJ et al (2006) Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson’s disease. Ann Neurol 59:298–309PubMedCrossRefGoogle Scholar
  160. 160.
    Njie EG, Boelen E, Stassen FR, Steinbusch HW, Borchelt DR, Streit WJ (2010) Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol Aging (in press, corrected proof)Google Scholar
  161. 161.
    Norris EH, Giasson BI, Lee VM (2004) Alpha-synuclein: normal function and role in neurodegenerative diseases. Curr Top Dev Biol 60:17–54PubMedCrossRefGoogle Scholar
  162. 162.
    Norton WT, Aquino DA, Hozumi I, Chiu FC, Brosnan CF (1992) Quantitative aspects of reactive gliosis: a review. Neurochem Res 17:877–885PubMedCrossRefGoogle Scholar
  163. 163.
    O’Sullivan SS, Massey LA, Williams DR et al (2008) Clinical outcomes of progressive supranuclear palsy and multiple system atrophy. Brain 131:1362–1372PubMedCrossRefGoogle Scholar
  164. 164.
    Orr CF, Rowe DB, Mizuno Y, Mori H, Halliday GM (2005) A possible role for humoral immunity in the pathogenesis of Parkinson’s disease. Brain 128:2665–2674PubMedCrossRefGoogle Scholar
  165. 165.
    Ozawa T, Okuizumi K, Ikeuchi T, Wakabayashi K, Takahashi H, Tsuji S (2001) Analysis of the expression level of alpha-synuclein mRNA using postmortem brain samples from pathologically confirmed cases of multiple system atrophy. Acta Neuropathol 102:188–190PubMedGoogle Scholar
  166. 166.
    Ozawa T, Paviour D, Quinn NP et al (2004) The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain 127:2657–2671PubMedCrossRefGoogle Scholar
  167. 167.
    Ozawa T, Takano H, Onodera O et al (1999) No mutation in the entire coding region of the alpha-synuclein gene in pathologically confirmed cases of multiple system atrophy. Neurosci Lett 270:110–112PubMedCrossRefGoogle Scholar
  168. 168.
    Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94:79–100PubMedCrossRefGoogle Scholar
  169. 169.
    Papp MI, Lantos PL (1994) The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 117(Pt 2):235–243PubMedCrossRefGoogle Scholar
  170. 170.
    Park JY, Paik SR, Jou I, Park SM (2008) Microglial phagocytosis is enhanced by monomeric alpha-synuclein, not aggregated alpha-synuclein: implications for Parkinson’s disease. Glia 56:1215–1223PubMedCrossRefGoogle Scholar
  171. 171.
    Parkkinen L, Kauppinen T, Pirttila T, Autere JM, Alafuzoff I (2005) Alpha-synuclein pathology does not predict extrapyramidal symptoms or dementia. Ann Neurol 57:82–91PubMedCrossRefGoogle Scholar
  172. 172.
    Peters A (2002) Structural changes in the normally aging cerebral cortex of primates. Prog Brain Res 136:455–465PubMedCrossRefGoogle Scholar
  173. 173.
    Polazzi E, Monti B (2010) Microglia and neuroprotection: from in vitro studies to therapeutic applications. Prog Neurobiol 92:293–315PubMedCrossRefGoogle Scholar
  174. 174.
    Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047PubMedCrossRefGoogle Scholar
  175. 175.
    Qian L, Flood PM (2008) Microglial cells and Parkinson’s disease. Immunol Res 41:155–164PubMedCrossRefGoogle Scholar
  176. 176.
    Qian L, Flood PM, Hong JS (2010) Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy. J Neural Transm 117:971–979PubMedCrossRefGoogle Scholar
  177. 177.
    Racette B (2008) A pilot clinical trial of creatine and minocycline in early Parkinson disease: 18-month results. Clin Neuropharmacol 31:141–150CrossRefGoogle Scholar
  178. 178.
    Raivich G, Bohatschek M, Kloss CU, Werner A, Jones LL, Kreutzberg GW (1999) Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Res Brain Res Rev 30:77–105PubMedCrossRefGoogle Scholar
  179. 179.
    Randy LH, Guoying B (2007) Agonism of peroxisome proliferator receptor-gamma may have therapeutic potential for neuroinflammation and Parkinson’s disease. Curr Neuropharmacol 5:35–46PubMedCrossRefGoogle Scholar
  180. 180.
    Rauen T, Taylor WR, Kuhlbrodt K, Wiessner M (1998) High-affinity glutamate transporters in the rat retina: a major role of the glial glutamate transporter GLAST-1 in transmitter clearance. Cell Tissue Res 291:19–31PubMedCrossRefGoogle Scholar
  181. 181.
    Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL (2007) Neuroprotective activities of CD4+ CD25+ regulatory T cells in an animal model of Parkinson’s disease. J Leukoc Biol 82:1083–1094PubMedCrossRefGoogle Scholar
  182. 182.
    Reynolds AD, Glanzer JG, Kadiu I et al (2008) Nitrated alpha-synuclein-activated microglial profiling for Parkinson’s disease. J Neurochem 104:1504–1525PubMedCrossRefGoogle Scholar
  183. 183.
    Reynolds AD, Kadiu I, Garg SK et al (2008) Nitrated alpha-synuclein and microglial neuroregulatory activities. J Neuroimmune Pharmacol 3:59–74PubMedCrossRefGoogle Scholar
  184. 184.
    Richter-Landsberg C, Gorath M, Trojanowski JQ, Lee VM (2000) alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res 62:9–14PubMedCrossRefGoogle Scholar
  185. 185.
    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 39:226–234PubMedCrossRefGoogle Scholar
  186. 186.
    Rohl C, Lucius R, Sievers J (2007) The effect of activated microglia on astrogliosis parameters in astrocyte cultures. Brain Res 1129:43–52PubMedCrossRefGoogle Scholar
  187. 187.
    Roodveldt C, Labrador-Garrido A, Gonzalez-Rey E et al (2010) Glial innate immunity generated by non-aggregated alpha-synuclein in mouse: differences between wild-type and Parkinson’s disease-linked mutants. PLoS One 5:e13481PubMedCrossRefGoogle Scholar
  188. 188.
    Ros-Bernal F, Hunot S, Herrero MT et al (2011) Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism. Proc Natl Acad Sci USA 108:6632–6637PubMedCrossRefGoogle Scholar
  189. 189.
    Rothstein JD, Dykes-Hoberg M, Pardo CA et al (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16:675–686PubMedCrossRefGoogle Scholar
  190. 190.
    Saavedra A, Baltazar G, Santos P, Carvalho CM, Duarte EP (2006) Selective injury to dopaminergic neurons up-regulates GDNF in substantia nigra postnatal cell cultures: role of neuron-glia crosstalk. Neurobiol Dis 23:533–542PubMedCrossRefGoogle Scholar
  191. 191.
    Samii A, Etminan M, Wiens MO, Jafari S (2009) NSAID use and the risk of Parkinson’s disease: systematic review and meta-analysis of observational studies. Drugs Aging 26:769–779PubMedCrossRefGoogle Scholar
  192. 192.
    Sanchez-Guajardo V, Febbraro F, Kirik D, Romero-Ramos M (2010) Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson’s disease. PLoS One 5:e8784PubMedCrossRefGoogle Scholar
  193. 193.
    Sandhu JK, Gardaneh M, Iwasiow R et al (2009) Astrocyte-secreted GDNF and glutathione antioxidant system protect neurons against 6OHDA cytotoxicity. Neurobiol Dis 33:405–414PubMedCrossRefGoogle Scholar
  194. 194.
    Savitt JM, Dawson VL, Dawson TM (2006) Diagnosis and treatment of Parkinson disease: molecules to medicine. J Clin Invest 116:1744–1754PubMedCrossRefGoogle Scholar
  195. 195.
    Schipper HM (2004) Brain iron deposition and the free radical-mitochondrial theory of ageing. Ageing Res Rev 3:265–301PubMedCrossRefGoogle Scholar
  196. 196.
    Schmidt S, Linnartz B, Mendritzki S et al (2011) Genetic mouse models for Parkinson’s disease display severe pathology in glial cell mitochondria. Hum Mol Genet 20:1197–1211PubMedCrossRefGoogle Scholar
  197. 197.
    Scholz SW, Houlden H, Schulte C et al (2009) SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol 65:610–614PubMedCrossRefGoogle Scholar
  198. 198.
    Schrag A, Ben-Shlomo Y, Quinn NP (1999) Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross-sectional study. Lancet 354:1771–1775PubMedCrossRefGoogle Scholar
  199. 199.
    Schrag A, Wenning GK, Quinn N, Ben-Shlomo Y (2008) Survival in multiple system atrophy. Mov Disord 23:294–296PubMedCrossRefGoogle Scholar
  200. 200.
    Schwartz JP, Nishiyama N (1994) Neurotrophic factor gene expression in astrocytes during development and following injury. Brain Res Bull 35:403–407PubMedCrossRefGoogle Scholar
  201. 201.
    Sheffield LG, Berman NE (1998) Microglial expression of MHC class II increases in normal aging of nonhuman primates. Neurobiol Aging 19:47–55PubMedCrossRefGoogle Scholar
  202. 202.
    Shimura H, Schlossmacher MG, Hattori N et al (2001) Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson’s disease. Science 293:263–269PubMedCrossRefGoogle Scholar
  203. 203.
    Shults CW, Rockenstein E, Crews L et al (2005) Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. J Neurosci 25:10689–10699PubMedCrossRefGoogle Scholar
  204. 204.
    Simard M, Nedergaard M (2004) The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 129:877–896PubMedCrossRefGoogle Scholar
  205. 205.
    Singleton AB, Farrer M, Johnson J et al (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841PubMedCrossRefGoogle Scholar
  206. 206.
    Sloane JA, Hinman JD, Lubonia M, Hollander W, Abraham CR (2003) Age-dependent myelin degeneration and proteolysis of oligodendrocyte proteins is associated with the activation of calpain-1 in the rhesus monkey. J Neurochem 84:157–168PubMedCrossRefGoogle Scholar
  207. 207.
    Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647PubMedCrossRefGoogle Scholar
  208. 208.
    Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35PubMedCrossRefGoogle Scholar
  209. 209.
    Soma H, Yabe I, Takei A, Fujiki N, Yanagihara T, Sasaki H (2006) Heredity in multiple system atrophy. J Neurol Sci 240:107–110PubMedCrossRefGoogle Scholar
  210. 210.
    Song YJ, Lundvig DM, Huang Y et al (2007) p25alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy. Am J Pathol 171:1291–1303PubMedCrossRefGoogle Scholar
  211. 211.
    Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M (1998) Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 251:205–208PubMedCrossRefGoogle Scholar
  212. 212.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840PubMedCrossRefGoogle Scholar
  213. 213.
    Stefanova N, Eriksson H, Georgievska B, Poewe W, Wenning GK (2010) Myeloperoxidase inhibition ameliorates multiple system atrophy-like degeneration in a transgenic mouse model. Mov Disord 25(Suppl. 3):625Google Scholar
  214. 214.
    Stefanova N, Hainzer M, Stemberger S et al (2009) Striatal transplantation for multiple system atrophy—are grafts affected by alpha-synucleinopathy? Exp Neurol 219:368–371PubMedCrossRefGoogle Scholar
  215. 215.
    Stefanova N, Klimaschewski L, Poewe W, Wenning GK, Reindl M (2001) Glial cell death induced by overexpression of alpha-synuclein. J Neurosci Res 65:432–438PubMedCrossRefGoogle Scholar
  216. 216.
    Stefanova N, Mitschnigg M, Ghorayeb I et al (2004) Failure of neuronal protection by inhibition of glial activation in a rat model of striatonigral degeneration. J Neurosci Res 78:87–91PubMedCrossRefGoogle Scholar
  217. 217.
    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 166:869–876PubMedCrossRefGoogle Scholar
  218. 218.
    Stefanova N, Reindl M, Neumann M, Kahle PJ, Poewe W, Wenning GK (2007) Microglial activation mediates neurodegeneration related to oligodendroglial alpha-synucleinopathy: implications for multiple system atrophy. Mov Disord 22:2196–2203PubMedCrossRefGoogle Scholar
  219. 219.
    Stefanova N, Schanda K, Klimaschewski L, Poewe W, Wenning GK, Reindl M (2003) Tumor necrosis factor-alpha-induced cell death in U373 cells overexpressing alpha-synuclein. J Neurosci Res 73:334–340PubMedCrossRefGoogle Scholar
  220. 220.
    Stefanova N, Stemberger S, Fellner L et al (2010) Disturbance of innate immunity linked to toll-like receptor 4 promotes neurodegeneration in a transgenic alpha-synucleinopathy model. Mov Disord 25(Suppl. 2):210–211Google Scholar
  221. 221.
    Stefanova N, Tison F, Reindl M, Poewe W, Wenning GK (2005) Animal models of multiple system atrophy. Trends Neurosci 28:501–506PubMedCrossRefGoogle Scholar
  222. 222.
    Stemberger S, Poewe W, Wenning GK, Stefanova N (2010) Targeted overexpression of human alpha-synuclein in oligodendroglia induces lesions linked to MSA-like progressive autonomic failure. Exp Neurol 224:459–464PubMedCrossRefGoogle Scholar
  223. 223.
    Stoll G, Jander S (1999) The role of microglia and macrophages in the pathophysiology of the CNS. Prog Neurobiol 58:233–247PubMedCrossRefGoogle Scholar
  224. 224.
    Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133–139PubMedCrossRefGoogle Scholar
  225. 225.
    Streit WJ (2004) Microglia and Alzheimer’s disease pathogenesis. J Neurosci Res 77:1–8PubMedCrossRefGoogle Scholar
  226. 226.
    Streit WJ, Sammons NW, Kuhns AJ, Sparks DL (2004) Dystrophic microglia in the aging human brain. Glia 45:208–212PubMedCrossRefGoogle Scholar
  227. 227.
    Su X, Federoff HJ, Maguire-Zeiss KA (2009) Mutant alpha-synuclein overexpression mediates early proinflammatory activity. Neurotox Res 16:238–254PubMedCrossRefGoogle Scholar
  228. 228.
    Su X, Maguire-Zeiss KA, Giuliano R, Prifti L, Venkatesh K, Federoff HJ (2008) Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol Aging 29:1690–1701PubMedCrossRefGoogle Scholar
  229. 229.
    Sugiyama I, Tanaka K, Akita M, Yoshida K, Kawase T, Asou H (2002) Ultrastructural analysis of the paranodal junction of myelinated fibers in 31-month-old-rats. J Neurosci Res 70:309–317PubMedCrossRefGoogle Scholar
  230. 230.
    Takahashi M, Tomizawa K, Fujita SC, Sato K, Uchida T, Imahori K (1993) A brain-specific protein p25 is localized and associated with oligodendrocytes, neuropil, and fiber-like structures of the CA3 hippocampal region in the rat brain. J Neurochem 60:228–235PubMedCrossRefGoogle Scholar
  231. 231.
    Tanaka J, Maeda N (1996) Microglial ramification requires nondiffusible factors derived from astrocytes. Exp Neurol 137:367–375PubMedCrossRefGoogle Scholar
  232. 232.
    Tanaka J, Okuma Y, Tomobe K, Nomura Y (2005) The age-related degeneration of oligodendrocytes in the hippocampus of the senescence-accelerated mouse (SAM) P8: a quantitative immunohistochemical study. Biol Pharm Bull 28:615–618PubMedCrossRefGoogle Scholar
  233. 233.
    Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37:510–518PubMedCrossRefGoogle Scholar
  234. 234.
    Taylor DL, Pirianov G, Holland S et al (2010) Attenuation of proliferation in oligodendrocyte precursor cells by activated microglia. J Neurosci Res 88:1632–1644PubMedCrossRefGoogle Scholar
  235. 235.
    Teismann P, Ferger B (2001) Inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2 provide neuroprotection in the MPTP-mouse model of Parkinson’s disease. Synapse 39:167–174PubMedCrossRefGoogle Scholar
  236. 236.
    Theodore S, Cao S, McLean PJ, Standaert DG (2008) Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J Neuropathol Exp Neurol 67:1149–1158PubMedCrossRefGoogle Scholar
  237. 237.
    Thorburne SK, Juurlink BH (1996) Low glutathione and high iron govern the susceptibility of oligodendroglial precursors to oxidative stress. J Neurochem 67:1014–1022PubMedCrossRefGoogle Scholar
  238. 238.
    Todorich B, Pasquini JM, Garcia CI, Paez PM, Connor JR (2009) Oligodendrocytes and myelination: the role of iron. Glia 57:467–478PubMedCrossRefGoogle Scholar
  239. 239.
    Tofaris GK, Razzaq A, Ghetti B, Lilley KS, Spillantini MG (2003) Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. J Biol Chem 278:44405–44411PubMedCrossRefGoogle Scholar
  240. 240.
    Togo T, Dickson DW (2002) Tau accumulation in astrocytes in progressive supranuclear palsy is a degenerative rather than a reactive process. Acta Neuropathol 104:398–402PubMedCrossRefGoogle Scholar
  241. 241.
    Trojanowski JQ, Revesz T (2007) Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol Appl Neurobiol 33:615–620PubMedCrossRefGoogle Scholar
  242. 242.
    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 29:259–268PubMedCrossRefGoogle Scholar
  243. 243.
    Ubhi K, Rockenstein E, Mante M et al (2010) Neurodegeneration in a transgenic mouse model of multiple system atrophy is associated with altered expression of oligodendroglial-derived neurotrophic factors. J Neurosci 30:6236–6246PubMedCrossRefGoogle Scholar
  244. 244.
    van Rossum D, Hanisch UK (2004) Microglia. Metab Brain Dis 19:393–411PubMedCrossRefGoogle Scholar
  245. 245.
    Verkhratsky A, Kettenmann H (1996) Calcium signalling in glial cells. Trends Neurosci 19:346–352PubMedCrossRefGoogle Scholar
  246. 246.
    Vila M, Jackson-Lewis V, Guegan C et al (2001) The role of glial cells in Parkinson’s disease. Curr Opin Neurol 14:483–489PubMedCrossRefGoogle Scholar
  247. 247.
    Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H (2000) NACP/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains. Acta Neuropathol 99:14–20PubMedCrossRefGoogle Scholar
  248. 248.
    Wakabayashi K, Takahashi H (2006) Cellular pathology in multiple system atrophy. Neuropathology 26:338–345PubMedCrossRefGoogle Scholar
  249. 249.
    Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H (1998) Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249:180–182PubMedCrossRefGoogle Scholar
  250. 250.
    Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980PubMedCrossRefGoogle Scholar
  251. 251.
    Wang X, Zhu S, Drozda M et al (2003) Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington’s disease. Proc Natl Acad Sci USA 100:10483–10487PubMedCrossRefGoogle Scholar
  252. 252.
    Wenning GK, Quinn N, Magalhaes M, Mathias C, Daniel SE (1994) “Minimal change” multiple system atrophy. Mov Disord 9:161–166PubMedCrossRefGoogle Scholar
  253. 253.
    Wenning GK, Stefanova N, Jellinger KA, Poewe W, Schlossmacher MG (2008) Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 64:239–246PubMedCrossRefGoogle Scholar
  254. 254.
    Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP (1997) Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord 12:133–147PubMedCrossRefGoogle Scholar
  255. 255.
    Wilhelmsson U, Bushong EA, Price DL et al (2006) Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc Natl Acad Sci USA 103:17513–17518PubMedCrossRefGoogle Scholar
  256. 256.
    Wu DC, Jackson-Lewis V, Vila M et al (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 22:1763–1771PubMedGoogle Scholar
  257. 257.
    Wullner U, Schmitt I, Kammal M, Kretzschmar HA, Neumann M (2009) Definite multiple system atrophy in a German family. J Neurol Neurosurg Psychiatry 80:449–450PubMedCrossRefGoogle Scholar
  258. 258.
    Yamada T, McGeer PL, McGeer EG (1992) Lewy bodies in Parkinson’s disease are recognized by antibodies to complement proteins. Acta Neuropathol 84:100–104PubMedCrossRefGoogle Scholar
  259. 259.
    Yamada T, McGeer PL, McGeer EG (1992) Some immunohistochemical features of argyrophilic grain dementia with normal cortical choline acetyltransferase levels but extensive subcortical pathology and markedly reduced dopamine. J Geriatr Psychiatry Neurol 5:3–13PubMedGoogle Scholar
  260. 260.
    Yao SY, Ljunggren-Rose A, Chandramohan N, Whetsell WO Jr, Sriram S (2010) In vitro and in vivo induction and activation of nNOS by LPS in oligodendrocytes. J Neuroimmunol 229:146–156PubMedCrossRefGoogle Scholar
  261. 261.
    Yazawa I, Giasson BI, Sasaki R et al (2005) Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45:847–859PubMedCrossRefGoogle Scholar
  262. 262.
    Zarranz JJ, Alegre J, Gomez-Esteban JC et al (2004) The new mutation, E46 K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173PubMedCrossRefGoogle Scholar
  263. 263.
    Zhang W, Wang T, Pei Z et al (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19:533–542PubMedCrossRefGoogle Scholar
  264. 264.
    Zhang X, Haaf M, Todorich B et al (2005) Cytokine toxicity to oligodendrocyte precursors is mediated by iron. Glia 52:199–208PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Lisa Fellner
    • 1
  • Kurt A. Jellinger
    • 2
  • Gregor K. Wenning
    • 1
  • Nadia Stefanova
    • 1
  1. 1.Division of Clinical Neurobiology, Department of NeurologyInnsbruck Medical UniversityInnsbruckAustria
  2. 2.Institute of Clinical NeurobiologyViennaAustria

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