The Role of Astrocytes in Parkinson’s Disease

  • Claire Stevens
  • Glenda Halliday


Unlike other disorders, astrocytes in regions undergoing neurodegeneration in patients with Parkinson’s disease do not become reactive. Instead gray matter protoplasmic astrocytes accumulate α-synuclein, withdraw their processes from damaged neurons, and show altered expression of constituent proteins, including PINK-1, parkin, and DJ-1 (gene products associated with recessive Parkinson’s disease). These and other gene products are normally up-regulated in astrocytes by disease states. Combined, these data suggest that protoplasmic astrocytes lose their protective function in patients with Parkinson’s disease, leaving neurons vulnerable to perturbations and insults they would normally be protected from. Recent work also shows that astrocytes are able to take up and metabolize L-DOPA, the drug of choice for standard therapy for Parkinson’s disease. It is therefore possible that ongoing astrocytic dysfunction may compromise the efficacy of L-DOPA therapy. These unique astrocytic responses to the disease process and current main therapy support the concept that astrocytes play a critical, under-recognized role in the initiation, progression, and treatment response of patients with Parkinson’s disease.


Amyotrophic Lateral Sclerosis Glial Fibrillary Acidic Protein Multiple System Atrophy Lewy Body Progressive Supranuclear Palsy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Oberheim NA, Takano T, Han X, He W, Lin JH, Wang F, et al. Uniquely hominid features of adult human astrocytes. J Neurosci. 2009;29:3276–87.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Lecrux C, Hamel E. The neurovascular unit in brain function and disease. Acta Physiol (Oxf). 2011;203:47–59.CrossRefGoogle Scholar
  4. 4.
    Rossi D, Martorana F, Brambilla L. Implications of gliotransmission for the pharmacotherapy of CNS disorders. CNS Drugs. 2011;25:641–58.PubMedCrossRefGoogle Scholar
  5. 5.
    Gordon GR, Mulligan SJ, MacVicar BA. Astrocyte control of the cerebrovasculature. Glia. 2007;55:1214–21.PubMedCrossRefGoogle Scholar
  6. 6.
    Iadecola C, Nedergaard M. Glial regulation of the cerebral microvasculature. Nat Neurosci. 2007;10:1369–76.PubMedCrossRefGoogle Scholar
  7. 7.
    Iacovetta C, Rudloff E, Kirby R. The role of aquaporin 4 in the brain. Vet Clin Pathol. 2012;41:32–44.PubMedGoogle Scholar
  8. 8.
    Jung JS, Bhat RV, Preston GM, Guggino WB, Baraban JM, Agre P. Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance. Proc Natl Acad Sci U S A. 1994;91:13052–6.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Jin BJ, Zhang H, Binder DK, Verkman AS. Aquaporin-4-dependent K(+) and water transport modeled in brain extracellular space following neuroexcitation. J Gen Physiol. 2013;141:119–32.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Song H, Stevens CF, Gage FH. Astroglia induce neurogenesis from adult neural stem cells. Nature. 2002;417:39–44.PubMedCrossRefGoogle Scholar
  11. 11.
    Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005;437:1370–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Barkho BZ, Song H, Aimone JB, Smrt RD, Kuwabara T, Nakashima K, et al. Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation. Stem Cells Dev. 2006;15:407–21.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Stevens B. Neuron-astrocyte signaling in the development and plasticity of neural circuits. Neurosignals. 2008;16:278–88.PubMedCrossRefGoogle Scholar
  14. 14.
    Ullian EM, Sapperstein SK, Christopherson KS, Barres BA. Control of synapse number by glia. Science. 2001;291:657–61.PubMedCrossRefGoogle Scholar
  15. 15.
    Nagler K, Mauch DH, Pfrieger FW. Glia-derived signals induce synapse formation in neurones of the rat central nervous system. J Physiol. 2001;533:665–79.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Liauw J, Hoang S, Choi M, Eroglu C, Choi M, Sun GH, et al. Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke. J Cereb Blood Flow Metab. 2008;28:1722–32.PubMedCrossRefGoogle Scholar
  17. 17.
    Risher WC, Eroglu C. Thrombospondins as key regulators of synaptogenesis in the central nervous system. Matrix Biol. 2012;31:170–7.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell. 2005;120:421–33.PubMedCrossRefGoogle Scholar
  19. 19.
    Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC, Otto A, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science. 2001;294:1354–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131:1164–78.PubMedCrossRefGoogle Scholar
  21. 21.
    Iino M, Goto K, Kakegawa W, Okado H, Sudo M, Ishiuchi S, et al. Glia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science. 2001;292:926–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Oliet SH, Piet R, Poulain DA. Control of glutamate clearance and synaptic efficacy by glial coverage of neurons. Science. 2001;292:923–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Smit AB, Syed NI, Schaap D, van Minnen J, Klumperman J, Kits KS, et al. A glia-derived acetylcholine-binding protein that modulates synaptic transmission. Nature. 2001;411:261–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Becker K. Innate and adaptive immune responses in CNS disease. Clin Neurosci Res. 2006;6:227–36.CrossRefGoogle Scholar
  25. 25.
    Farina C, Aloisi F, Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol. 2007;28:138–45.PubMedCrossRefGoogle Scholar
  26. 26.
    Maragakis NJ, Rothstein JD. Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol. 2006;2:679–89.PubMedCrossRefGoogle Scholar
  27. 27.
    Wilhelmsson U, Li L, Pekna M, Berthold CH, Blom S, Eliasson C, et al. Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci. 2004;24:5016–21.PubMedCrossRefGoogle Scholar
  28. 28.
    Menet V, Prieto M, Privat A, Gimenez y Ribotta M. Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes. Proc Natl Acad Sci U S A. 2003;100:8999–9004.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Kinouchi R, Takeda M, Yang L, Wilhelmsson U, Lundkvist A, Pekny M, et al. Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin. Nat Neurosci. 2003;6:863–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Widestrand A, Faijerson J, Wilhelmsson U, Smith PL, Li L, Sihlbom C, et al. Increased neurogenesis and astrogenesis from neural progenitor cells grafted in the hippocampus of GFAP−/− Vim−/− mice. Stem Cells. 2007;25:2619–27.PubMedCrossRefGoogle Scholar
  31. 31.
    Eng LF, Lee YL, Kwan H, Brenner M, Messing A. Astrocytes cultured from transgenic mice carrying the added human glial fibrillary acidic protein gene contain Rosenthal fibers. J Neurosci Res. 1998;53:353–60.PubMedCrossRefGoogle Scholar
  32. 32.
    Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science. 1997;276:1699–702.PubMedCrossRefGoogle Scholar
  33. 33.
    Double KL, Reyes S, Werry EL, Halliday GM. Selective cell death in neurodegeneration: why are some neurons spared in vulnerable regions? Prog Neurobiol. 2010;92:316–29.PubMedCrossRefGoogle Scholar
  34. 34.
    Tolnay M, Probst A. The neuropathological spectrum of neurodegenerative tauopathies. IUBMB Life. 2003;55:299–305.PubMedCrossRefGoogle Scholar
  35. 35.
    Kwong LK, Uryu K, Trojanowski JQ, Lee VM. TDP-43 proteinopathies: neurodegenerative protein misfolding diseases without amyloidosis. Neurosignals. 2008;16:41–51.PubMedCrossRefGoogle Scholar
  36. 36.
    Jellinger KA. Neuropathological spectrum of synucleinopathies. Mov Disord. 2003;18 Suppl 6:S2–12.PubMedCrossRefGoogle Scholar
  37. 37.
    Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev. 2001;81:741–66.PubMedGoogle Scholar
  38. 38.
    Beach TG, McGeer EG. Lamina-specific arrangement of astrocytic gliosis and senile plaques in Alzheimer’s disease visual cortex. Brain Res. 1988;463:357–61.PubMedCrossRefGoogle Scholar
  39. 39.
    Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989;86:7611–5.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Kashon ML, Ross GW, O’Callaghan JP, Miller DB, Petrovitch H, Burchfiel CM, et al. Associations of cortical astrogliosis with cognitive performance and dementia status. J Alzheimers Dis. 2004;6:595–604. discussion 73–81.PubMedGoogle Scholar
  41. 41.
    Wisniewski HM, Wegiel J. Spatial relationships between astrocytes and classical plaque components. Neurobiol Aging. 1991;12:593–600.PubMedCrossRefGoogle Scholar
  42. 42.
    Allaman I, Gavillet M, Belanger M, Laroche T, Viertl D, Lashuel HA, et al. Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability. J Neurosci. 2010;30:3326–38.PubMedCrossRefGoogle Scholar
  43. 43.
    Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W. Astrocytes are important mediators of Abeta-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis. 2011;2:e167.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Matsunaga W, Shirokawa T, Isobe K. Specific uptake of Abeta1-40 in rat brain occurs in astrocyte, but not in microglia. Neurosci Lett. 2003;342:129–31.PubMedCrossRefGoogle Scholar
  45. 45.
    Funato H, Yoshimura M, Yamazaki T, Saido TC, Ito Y, Yokofujita J, et al. Astrocytes containing amyloid beta-protein (Abeta)-positive granules are associated with Abeta40-positive diffuse plaques in the aged human brain. Am J Pathol. 1998;152:983–92.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Song YJ, Halliday GM, Holton JL, Lashley T, O’Sullivan SS, McCann H, et al. Degeneration in different parkinsonian syndromes relates to astrocyte type and astrocyte protein expression. J Neuropathol Exp Neurol. 2009;68:1073–83.PubMedCrossRefGoogle Scholar
  47. 47.
    Dickson DW, Ksiezak-Reding H, Liu WK, Davies P, Crowe A, Yen SH. Immunocytochemistry of neurofibrillary tangles with antibodies to subregions of tau protein: identification of hidden and cleaved tau epitopes and a new phosphorylation site. Acta Neuropathol. 1992;84:596–605.PubMedGoogle Scholar
  48. 48.
    Papasozomenos SC, Binder LI. Phosphorylation determines two distinct species of tau in the central nervous system. Cell Motil Cytoskeleton. 1987;8:210–26.PubMedCrossRefGoogle Scholar
  49. 49.
    Komori T. Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Brain Pathol. 1999;9:663–79.PubMedCrossRefGoogle Scholar
  50. 50.
    Ikeda K, Akiyama H, Arai T, Nishimura T. Glial tau pathology in neurodegenerative diseases: their nature and comparison with neuronal tangles. Neurobiol Aging. 1998;19:S85–91.PubMedCrossRefGoogle Scholar
  51. 51.
    Forman MS, Lal D, Zhang B, Dabir DV, Swanson E, Lee VM, et al. Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration. J Neurosci. 2005;25:3539–50.PubMedCrossRefGoogle Scholar
  52. 52.
    Dabir DV, Robinson MB, Swanson E, Zhang B, Trojanowski JQ, Lee VM, et al. Impaired glutamate transport in a mouse model of tau pathology in astrocytes. J Neurosci. 2006;26:644–54.PubMedCrossRefGoogle Scholar
  53. 53.
    Gordon PH. Amyotrophic lateral sclerosis: an update for 2013 clinical features, pathophysiology, management and therapeutic trials. Aging Dis. 2013;4:295–310.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Warren JD, Rohrer JD, Rossor MN. Clinical review. Frontotemporal dementia. BMJ. 2013;347:f4827.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Kushner PD, Stephenson DT, Wright S. Reactive astrogliosis is widespread in the subcortical white matter of amyotrophic lateral sclerosis brain. J Neuropathol Exp Neurol. 1991;50:263–77.PubMedCrossRefGoogle Scholar
  56. 56.
    Nagy D, Kato T, Kushner PD. Reactive astrocytes are widespread in the cortical gray matter of amyotrophic lateral sclerosis. J Neurosci Res. 1994;38:336–47.PubMedCrossRefGoogle Scholar
  57. 57.
    Schiffer D, Cordera S, Cavalla P, Migheli A. Reactive astrogliosis of the spinal cord in amyotrophic lateral sclerosis. J Neurol Sci. 1996;139(Suppl):27–33.PubMedCrossRefGoogle Scholar
  58. 58.
    Lin WL, Castanedes-Casey M, Dickson DW. Transactivation response DNA-binding protein 43 microvasculopathy in frontotemporal degeneration and familial Lewy body disease. J Neuropathol Exp Neurol. 2009;68:1167–76.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, Gage FH. Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell. 2008;3:649–57.PubMedCrossRefGoogle Scholar
  60. 60.
    Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71:670–6.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Sekiyama K, Sugama S, Fujita M, Sekigawa A, Takamatsu Y, Waragai M, et al. Neuroinflammation in Parkinson’s disease and related disorders: a lesson from genetically manipulated mouse models of alpha-synucleinopathies. Parkinsons Dis. 2012;2012:271732.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Niranjan R. The role of inflammatory and oxidative stress mechanisms in the pathogenesis of Parkinson’s disease: focus on astrocytes. Mol Neurobiol. 2014;49(1):28–38.PubMedCrossRefGoogle Scholar
  63. 63.
    Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol. 1999;56:33–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Betarbet R, Sherer TB, Greenamyre JT. Animal models of Parkinson’s disease. Bioessays. 2002;24:308–18.PubMedCrossRefGoogle Scholar
  65. 65.
    Schober A. Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP. Cell Tissue Res. 2004;318:215–24.PubMedCrossRefGoogle Scholar
  66. 66.
    Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D. Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol. 1999;46:598–605.PubMedCrossRefGoogle Scholar
  67. 67.
    Norazit A, Meedeniya AC, Nguyen MN, Mackay-Sim A. Progressive loss of dopaminergic neurons induced by unilateral rotenone infusion into the medial forebrain bundle. Brain Res. 2010;1360:119–29.PubMedCrossRefGoogle Scholar
  68. 68.
    Sherer TB, Betarbet R, Kim JH, Greenamyre JT. Selective microglial activation in the rat rotenone model of Parkinson’s disease. Neurosci Lett. 2003;341:87–90.PubMedCrossRefGoogle Scholar
  69. 69.
    Halliday GM, Stevens CH. Glia: initiators and progressors of pathology in Parkinson’s disease. Mov Disord. 2011;26:6–17.PubMedCrossRefGoogle Scholar
  70. 70.
    Braak H, Sastre M, Del Tredici K. Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease. Acta Neuropathol. 2007;114:231–41.PubMedCrossRefGoogle Scholar
  71. 71.
    Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S, et al. Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem. 2010;285:9262–72.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Knott C, Wilkin GP, Stern G. Astrocytes and microglia in the substantia nigra and caudate-putamen in Parkinson’s disease. Parkinsonism Relat Disord. 1999;5:115–22.PubMedCrossRefGoogle Scholar
  73. 73.
    Nomura T, Yabe T, Rosenthal ES, Krzan M, Schwartz JP. PSA-NCAM distinguishes reactive astrocytes in 6-OHDA-lesioned substantia nigra from those in the striatal terminal fields. J Neurosci Res. 2000;61:588–96.PubMedCrossRefGoogle Scholar
  74. 74.
    Wachter B, Schurger S, Rolinger J, von Ameln-Mayerhofer A, Berg D, Wagner HJ, et al. Effect of 6-hydroxydopamine (6-OHDA) on proliferation of glial cells in the rat cortex and striatum: evidence for de-differentiation of resident astrocytes. Cell Tissue Res. 2010;342:147–60.PubMedCrossRefGoogle Scholar
  75. 75.
    Gu XL, Long CX, Sun L, Xie C, Lin X, Cai H. Astrocytic expression of Parkinson’s disease-related A53T alpha-synuclein causes neurodegeneration in mice. Mol Brain. 2010;3:12.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Mythri RB, Venkateshappa C, Harish G, Mahadevan A, Muthane UB, Yasha TC, et al. Evaluation of markers of oxidative stress, antioxidant function and astrocytic proliferation in the striatum and frontal cortex of Parkinson’s disease brains. Neurochem Res. 2011;36:1452–63.PubMedCrossRefGoogle Scholar
  77. 77.
    Mirza B, Hadberg H, Thomsen P, Moos T. The absence of reactive astrogliosis is indicative of a unique inflammatory process in Parkinson’s disease. Neuroscience. 2000;95:425–32.PubMedCrossRefGoogle Scholar
  78. 78.
    Colombo E, Cordiglieri C, Melli G, Newcombe J, Krumbholz M, Parada LF, et al. Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration. J Exp Med. 2012;209:521–35.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Kimura N, Takahashi M, Tashiro T, Terao K. Amyloid beta up-regulates brain-derived neurotrophic factor production from astrocytes: rescue from amyloid beta-related neuritic degeneration. J Neurosci Res. 2006;84:782–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Wang L, Lin F, Wang J, Wu J, Han R, Zhu L, et al. Truncated N-terminal huntingtin fragment with expanded-polyglutamine (htt552-100Q) suppresses brain-derived neurotrophic factor transcription in astrocytes. Acta Biochim Biophys Sin (Shanghai). 2012;44:249–58.CrossRefGoogle Scholar
  81. 81.
    Hu J, Ferreira A, Van Eldik LJ. S100beta induces neuronal cell death through nitric oxide release from astrocytes. J Neurochem. 1997;69:2294–301.PubMedCrossRefGoogle Scholar
  82. 82.
    Li Y, Barger SW, Liu L, Mrak RE, Griffin WS. S100beta induction of the proinflammatory cytokine interleukin-6 in neurons. J Neurochem. 2000;74:143–50.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Sorci G, Bianchi R, Riuzzi F, Tubaro C, Arcuri C, Giambanco I, et al. S100B protein, a damage-associated molecular pattern protein in the brain and heart, and beyond. Cardiovasc Psychiatry Neurol. 2010;2010.Google Scholar
  84. 84.
    Sathe K, Maetzler W, Lang JD, Mounsey RB, Fleckenstein C, Martin HL, et al. S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-alpha pathway. Brain. 2012;135:3336–47.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Gandhi S, Muqit MM, Stanyer L, Healy DG, Abou-Sleiman PM, Hargreaves I, et al. PINK1 protein in normal human brain and Parkinson’s disease. Brain. 2006;129:1720–31.PubMedCrossRefGoogle Scholar
  86. 86.
    Bandopadhyay R, Kingsbury AE, Cookson MR, Reid AR, Evans IM, Hope AD, et al. The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson’s disease. Brain. 2004;127:420–30.PubMedCrossRefGoogle Scholar
  87. 87.
    Zarate-Lagunes M, Gu WJ, Blanchard V, Francois C, Muriel MP, Mouatt-Prigent A, et al. Parkin immunoreactivity in the brain of human and non-human primates: an immunohistochemical analysis in normal conditions and in Parkinsonian syndromes. J Comp Neurol. 2001;432:184–96.PubMedCrossRefGoogle Scholar
  88. 88.
    Ledesma MD, Galvan C, Hellias B, Dotti C, Jensen PH. Astrocytic but not neuronal increased expression and redistribution of parkin during unfolded protein stress. J Neurochem. 2002;83:1431–40.PubMedCrossRefGoogle Scholar
  89. 89.
    Mullett SJ, Hamilton RL, Hinkle DA. DJ-1 immunoreactivity in human brain astrocytes is dependent on infarct presence and infarct age. Neuropathology. 2009;29:125–31.PubMedCrossRefGoogle Scholar
  90. 90.
    Taylor JM, Wu RM, Farrer MJ, Delatycki MB, Lockhart PJ. Analysis of PArkin co-regulated gene in a Taiwanese-ethnic Chinese cohort with early-onset Parkinson’s disease. Parkinsonism Relat Disord. 2009;15:417–21.PubMedCrossRefGoogle Scholar
  91. 91.
    Schmidt S, Linnartz B, Mendritzki S, Sczepan T, Lubbert M, Stichel CC, et al. Genetic mouse models for Parkinson’s disease display severe pathology in glial cell mitochondria. Hum Mol Genet. 2011;20:1197–211.PubMedCrossRefGoogle Scholar
  92. 92.
    Choi I, Kim J, Jeong HK, Kim B, Jou I, Park SM, et al. PINK1 deficiency attenuates astrocyte proliferation through mitochondrial dysfunction, reduced AKT and increased p38 MAPK activation, and downregulation of EGFR. Glia. 2013;61:800–12.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Waak J, Weber SS, Waldenmaier A, Gorner K, Alunni-Fabbroni M, Schell H, et al. Regulation of astrocyte inflammatory responses by the Parkinson’s disease-associated gene DJ-1. FASEB J. 2009;23:2478–89.PubMedCrossRefGoogle Scholar
  94. 94.
    Lev N, Barhum Y, Ben-Zur T, Melamed E, Steiner I, Offen D. Knocking out DJ-1 attenuates astrocytes neuroprotection against 6-hydroxydopamine toxicity. J Mol Neurosci. 2013;50:542–50.PubMedCrossRefGoogle Scholar
  95. 95.
    Kim JH, Choi DJ, Jeong HK, Kim J, Kim DW, Choi SY, et al. DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1, in brain microglia and astrocytes: a novel anti-inflammatory function of DJ-1. Neurobiol Dis. 2013;60:1–10.PubMedCrossRefGoogle Scholar
  96. 96.
    Braidy N, Gai WP, Xu YH, Sachdev P, Guillemin GJ, Jiang XM, et al. Uptake and mitochondrial dysfunction of alpha-synuclein in human astrocytes, cortical neurons and fibroblasts. Transl Neurodegener. 2013;2:20.PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Lu M, Sun XL, Qiao C, Liu Y, Ding JH, Hu G. Uncoupling protein 2 deficiency aggravates astrocytic endoplasmic reticulum stress and nod-like receptor protein 3 inflammasome activation. Neurobiol Aging. 2014;35(2):421–30.PubMedCrossRefGoogle Scholar
  98. 98.
    Inden M, Kitamura Y, Takahashi K, Takata K, Ito N, Niwa R, et al. Protection against dopaminergic neurodegeneration in Parkinson’s disease-model animals by a modulator of the oxidized form of DJ-1, a wild-type of familial Parkinson’s disease-linked PARK7. J Pharmacol Sci. 2011;117:189–203.PubMedCrossRefGoogle Scholar
  99. 99.
    Papkovskaia TD, Chau KY, Inesta-Vaquera F, Papkovsky DB, Healy DG, Nishio K, et al. G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization. Hum Mol Genet. 2012;21:4201–13.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Jin J, Meredith GE, Chen L, Zhou Y, Xu J, Shie FS, et al. Quantitative proteomic analysis of mitochondrial proteins: relevance to Lewy body formation and Parkinson’s disease. Brain Res Mol Brain Res. 2005;134:119–38.PubMedCrossRefGoogle Scholar
  101. 101.
    Schlossmacher MG, Frosch MP, Gai WP, Medina M, Sharma N, Forno L, et al. Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies. Am J Pathol. 2002;160:1655–67.PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Murakami T, Shoji M, Imai Y, Inoue H, Kawarabayashi T, Matsubara E, et al. Pael-R is accumulated in Lewy bodies of Parkinson’s disease. Ann Neurol. 2004;55:439–42.PubMedCrossRefGoogle Scholar
  103. 103.
    Durrenberger PF, Filiou MD, Moran LB, Michael GJ, Novoselov S, Cheetham ME, et al. DnaJB6 is present in the core of Lewy bodies and is highly up-regulated in parkinsonian astrocytes. J Neurosci Res. 2009;87:238–45.PubMedCrossRefGoogle Scholar
  104. 104.
    Power JH, Shannon JM, Blumbergs PC, Gai WP. Nonselenium glutathione peroxidase in human brain: elevated levels in Parkinson’s disease and dementia with Lewy bodies. Am J Pathol. 2002;161:885–94.PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Chuang JZ, Zhou H, Zhu M, Li SH, Li XJ, Sung CH. Characterization of a brain-enriched chaperone, MRJ, that inhibits Huntingtin aggregation and toxicity independently. J Biol Chem. 2002;277:19831–8.PubMedCrossRefGoogle Scholar
  106. 106.
    Michael GJ, Esmailzadeh S, Moran LB, Christian L, Pearce RK, Graeber MB. Up-regulation of metallothionein gene expression in parkinsonian astrocytes. Neurogenetics. 2011;12:295–305.PubMedCrossRefGoogle Scholar
  107. 107.
    Futakawa N, Kondoh M, Ueda S, Higashimoto M, Takiguchi M, Suzuki S, et al. Involvement of oxidative stress in the synthesis of metallothionein induced by mitochondrial inhibitors. Biol Pharm Bull. 2006;29:2016–20.PubMedCrossRefGoogle Scholar
  108. 108.
    Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, et al. Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol. 1994;36:348–55.PubMedCrossRefGoogle Scholar
  109. 109.
    Fernandez HH. Updates in the medical management of Parkinson disease. Cleve Clin J Med. 2012;79:28–35.PubMedCrossRefGoogle Scholar
  110. 110.
    Inyushin MY, Huertas A, Kucheryavykh YV, Kucheryavykh LY, Tsydzik V, Sanabria P, et al. L-DOPA uptake in astrocytic endfeet enwrapping blood vessels in rat brain. Parkinsons Dis. 2012;2012:321406.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Claire Stevens
    • 1
  • Glenda Halliday
    • 1
  1. 1.Department of Medicine, and Neuroscience Research AustraliaUniversity of New South WalesRandwickAustralia

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