Skip to main content

Advertisement

SpringerLink
Log in

Glial cells in Parkinson´s disease: protective or deleterious?

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Glial cells have been identified more than 100 years ago, and are known to play a key role in the central nervous system (CNS) function. A recent piece of evidence is emerging showing that in addition to the capacity of CNS modulation and homeostasis, glial cells are also being looked like as a promising cell source not only to study CNS pathologies initiation and progression but also to the establishment and development of new therapeutic strategies. Thus, in the present review, we will discuss the current evidence regarding glial cells’ contribution to neurodegenerative diseases as Parkinson’s disease, providing cellular, molecular, functional, and behavioral data supporting its active role in disease initiation, progression, and treatment. As so, considering their functional relevance, glial cells may be important to the understanding of the underlying mechanisms regarding neuronal-glial networks in neurodegeneration/regeneration processes, which may open new research opportunities for their future use as a target or treatment in human clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Pringsheim T, Jette N, Frolkis A, Steeves TDL (2014) The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord Off J Mov Disord Soc 29:1583–1590. https://doi.org/10.1002/mds.25945

    Article  Google Scholar 

  2. Kim HJ, Kim H-J, Lee J-Y et al (2011) Phenotype analysis in patients with early onset Parkinson’s disease with and without parkin mutations. J Neurol 258:2260–2267. https://doi.org/10.1007/s00415-011-6110-1

    Article  CAS  PubMed  Google Scholar 

  3. Lees AJ, Hardy J, Revesz T (2009) Parkinson’s disease Lancet. Lond Engl 373:2055–2066. https://doi.org/10.1016/S0140-6736(09)60492-X

    Article  CAS  Google Scholar 

  4. Poewe W, Seppi K, Tanner CM et al (2017) Parkinson disease. Nat Rev Dis Primer 3:17013. https://doi.org/10.1038/nrdp.2017.13

    Article  Google Scholar 

  5. Langston JW (2006) The Parkinson’s complex: parkinsonism is just the tip of the iceberg. Ann Neurol 59:591–596. https://doi.org/10.1002/ana.20834

    Article  PubMed  Google Scholar 

  6. Rodriguez MC, Guridi OJ, Alvarez L et al (1998) The subthalamic nucleus and tremor in Parkinson’s disease. Mov Disord Off J Mov Disord Soc 13(Suppl 3):111–118. https://doi.org/10.1002/mds.870131320

    Article  Google Scholar 

  7. Dujardin K, Degreef JF, Rogelet P et al (1999) Impairment of the supervisory attentional system in early untreated patients with Parkinson’s disease. J Neurol 246:783–788

    Article  CAS  PubMed  Google Scholar 

  8. Owens-Walton C, Jakabek D, Li X et al (2018) Striatal changes in Parkinson disease: an investigation of morphology, functional connectivity and their relationship to clinical symptoms. Psychiatry Res. https://doi.org/10.1016/j.pscychresns.2018.03.004

    Article  Google Scholar 

  9. Daniel W, Burn DJ (2011) Parkinson’s disease: the quintessential neuropsychiatric disorder. Mov Disord 26:1022–1031. https://doi.org/10.1002/mds.23664

    Article  Google Scholar 

  10. LeWitt PA, Fahn S (2016) Levodopa therapy for Parkinson disease: a look backward and forward. Neurology 86:S3–12. https://doi.org/10.1212/WNL.0000000000002509

    Article  CAS  PubMed  Google Scholar 

  11. Jankovic J, Aguilar LG (2008) Current approaches to the treatment of Parkinson’s disease. Neuropsychiatr Dis Treat 4:743–757. https://doi.org/10.2147/ndt.s2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rascol O, Payoux P, Ory F et al (2003) Limitations of current Parkinson’s disease therapy. Ann Neurol 53(Suppl 3):S3–12. https://doi.org/10.1002/ana.10513(discussion S12–15)

    Article  CAS  PubMed  Google Scholar 

  13. Jimenez-Shahed J, Telkes I, Viswanathan A, Ince NF (2016) GPi oscillatory activity differentiates tics from the resting state, voluntary movements, and the unmedicated Parkinsonian state. Front Neurosci 10:436. https://doi.org/10.3389/fnins.2016.00436

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dexter DT, Jenner P (2013) Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med 62:132–144. https://doi.org/10.1016/j.freeradbiomed.2013.01.018

    Article  CAS  PubMed  Google Scholar 

  15. Cattaneo C, Jost WH, Bonizzoni E (2020) Long-term efficacy of safinamide on symptoms severity and quality of life in fluctuating Parkinson’s disease patients. J Park Dis 10:89–97. https://doi.org/10.3233/JPD-191765

    Article  Google Scholar 

  16. Borgohain R, Szasz J, Stanzione P et al (2014) Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with motor fluctuations. Mov Disord 29:229–237. https://doi.org/10.1002/mds.25751

    Article  CAS  PubMed  Google Scholar 

  17. Teixeira FG, Gago MF, Marques P et al (2018) Safinamide: a new hope for Parkinson’s disease? Drug Discov Today 23:736–744. https://doi.org/10.1016/j.drudis.2018.01.033

    Article  CAS  PubMed  Google Scholar 

  18. Okun MS (2012) Deep-brain stimulation for Parkinson’s disease. N Engl J Med 367:1529–1538. https://doi.org/10.1056/NEJMct1208070

    Article  CAS  PubMed  Google Scholar 

  19. Moro E, Lozano AM, Pollak P et al (2010) Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson’s disease. Mov Disord 25:578–586. https://doi.org/10.1002/mds.22735

    Article  PubMed  Google Scholar 

  20. Strutt AM, Simpson R, Jankovic J, York MK (2012) Changes in cognitive-emotional and physiological symptoms of depression following STN-DBS for the treatment of Parkinson’s disease. Eur J Neurol 19:121–127. https://doi.org/10.1111/j.1468-1331.2011.03447.x

    Article  CAS  PubMed  Google Scholar 

  21. Taba HA, Wu SS, Foote KD et al (2010) A closer look at unilateral versus bilateral deep brain stimulation: results of the National Institutes of Health COMPARE cohort. J Neurosurg 113:1224–1229. https://doi.org/10.3171/2010.8.JNS10312

    Article  PubMed  Google Scholar 

  22. Coleman RR, Kotagal V, Patil PG, Chou KL (2014) Validity and efficacy of screening algorithms for assessing deep brain stimulation candidacy in Parkinson disease. Mov Disord Clin Pract 1:342–347. https://doi.org/10.1002/mdc3.12103

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hamberg K, Hariz G-M (2014) The decision-making process leading to deep brain stimulation in men and women with Parkinson’s disease—an interview study. BMC Neurol 14:89. https://doi.org/10.1186/1471-2377-14-89

    Article  PubMed  PubMed Central  Google Scholar 

  24. Morishita T, Rahman M, Foote KD et al (2011) DBS candidates that fall short on a levodopa challenge test: alternative and important indications. The Neurologist 17:263–268. https://doi.org/10.1097/NRL.0b013e31822d1069

    Article  PubMed  PubMed Central  Google Scholar 

  25. Brederlau A, Correia AS, Anisimov SV et al (2006) Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson’s disease: effect of in vitro differentiation on graft survival and teratoma formation. Stem Cells Dayt Ohio 24:1433–1440. https://doi.org/10.1634/stemcells.2005-0393

    Article  CAS  Google Scholar 

  26. Daadi MM, Grueter BA, Malenka RC et al (2012) Dopaminergic neurons from midbrain-specified human embryonic stem cell-derived neural stem cells engrafted in a monkey model of Parkinson’s disease. PLoS ONE 7:e41120. https://doi.org/10.1371/journal.pone.0041120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang Z, Wang X, Wang S (2008) Isolation and characterization of mesenchymal stem cells derived from bone marrow of patients with Parkinson’s disease. Vitro Cell Dev Biol Anim 44:169–177. https://doi.org/10.1007/s11626-008-9093-1

    Article  CAS  Google Scholar 

  28. Savchenko E, Marote A, Russ K et al (2018) Generation of a human induced pluripotent stem cell line (CSC-42) from a patient with sporadic form of Parkinson’s disease. Stem Cell Res 27:78–81. https://doi.org/10.1016/j.scr.2018.01.002

    Article  CAS  PubMed  Google Scholar 

  29. Goodarzi P, Aghayan HR, Larijani B et al (2015) Stem cell-based approach for the treatment of Parkinson’s disease. Med J Islam Repub Iran 29:168

    PubMed  PubMed Central  Google Scholar 

  30. Pires AO, Teixeira FG, Mendes-Pinheiro B et al (2017) Old and new challenges in Parkinson’s disease therapeutics. Prog Neurobiol 156:69–89. https://doi.org/10.1016/j.pneurobio.2017.04.006

    Article  CAS  PubMed  Google Scholar 

  31. Zhang Q, Chen W, Tan S, Lin T (2016) Stem cells for modeling and therapy of Parkinson’s disease. Hum Gene Ther 28:85–98. https://doi.org/10.1089/hum.2016.116

    Article  CAS  PubMed  Google Scholar 

  32. Bradl M, Lassmann H (2010) Oligodendrocytes: biology and pathology. Acta Neuropathol (Berl) 119:37–53. https://doi.org/10.1007/s00401-009-0601-5

    Article  Google Scholar 

  33. Liu B, Hong J-S (2003) Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304:1–7. https://doi.org/10.1124/jpet.102.035048

    Article  CAS  PubMed  Google Scholar 

  34. Mena MA, García de Yébenes J (2008) Glial cells as players in parkinsonism: the “good”, the “bad”, and the “mysterious” glia. Neurosci Rev J Bringing Neurobiol Neurol Psychiatry 14:544–560. https://doi.org/10.1177/1073858408322839

    Article  CAS  Google Scholar 

  35. Wang J, Song N, Jiang H et al (2013) Pro-inflammatory cytokines modulate iron regulatory protein 1 expression and iron transportation through reactive oxygen/nitrogen species production in ventral mesencephalic neurons. Biochim Biophys Acta 1832:618–625. https://doi.org/10.1016/j.bbadis.2013.01.021

    Article  CAS  PubMed  Google Scholar 

  36. De Miranda BR, Rocha EM, Bai Q et al (2018) Astrocyte-specific DJ-1 overexpression protects against rotenone-induced neurotoxicity in a rat model of Parkinson’s disease. Neurobiol Dis 115:101–114. https://doi.org/10.1016/j.nbd.2018.04.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Halliday GM, Stevens CH (2011) Glia: initiators and progressors of pathology in Parkinson’s disease. Mov Disord Off J Mov Disord Soc 26:6–17. https://doi.org/10.1002/mds.23455

    Article  Google Scholar 

  38. Yue P, Gao L, Wang X et al (2018) Pretreatment of glial cell-derived neurotrophic factor and geranylgeranylacetone ameliorates brain injury in Parkinson’s disease by its anti-apoptotic and anti-oxidative property. J Cell Biochem 119:5491–5502. https://doi.org/10.1002/jcb.26712

    Article  CAS  PubMed  Google Scholar 

  39. Jäkel S, Dimou L (2017) Glial cells and their function in the adult brain: a journey through the history of their ablation. Front Cell Neurosci 11:24. https://doi.org/10.3389/fncel.2017.00024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Weinhard L, di Bartolomei G, Bolasco G et al (2018) Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat Commun 9:1228. https://doi.org/10.1038/s41467-018-03566-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Miyamoto A, Wake H, Ishikawa AW et al (2016) Microglia contact induces synapse formation in developing somatosensory cortex. Nat Commun 7:1–12. https://doi.org/10.1038/ncomms12540

    Article  CAS  Google Scholar 

  42. Bitzer-Quintero OK, González-Burgos I (2012) Immune system in the brain: a modulatory role on dendritic spine morphophysiology? In: Neural Plast. https://www.hindawi.com/journals/np/2012/348642/. Accessed 7 Mar 2018

  43. Jha MK, Kim J-H, Song GJ et al (2017) Functional dissection of astrocyte-secreted proteins: implications in brain health and diseases. Prog Neurobiol. https://doi.org/10.1016/j.pneurobio.2017.12.003

    Article  PubMed  Google Scholar 

  44. Vinet J, van Weering HRJ, Heinrich A et al (2012) Neuroprotective function for ramified microglia in hippocampal excitotoxicity. J Neuroinflammation 9:27. https://doi.org/10.1186/1742-2094-9-27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fields RD, Stevens-Graham B (2002) New insights into neuron-glia communication. Science 298:556–562. https://doi.org/10.1126/science.298.5593.556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Min R, Nevian T (2012) Astrocyte signaling controls spike timing-dependent depression at neocortical synapses. Nat Neurosci 15:746–753. https://doi.org/10.1038/nn.3075

    Article  CAS  PubMed  Google Scholar 

  47. Araque A, Li N, Doyle RT, Haydon PG (2000) SNARE protein-dependent glutamate release from astrocytes. J Neurosci 20:666–673. https://doi.org/10.1523/JNEUROSCI.20-02-00666.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Savtchouk I, Volterra A (2018) Gliotransmission: beyond black-and-white. J Neurosci Off J Soc Neurosci 38:14–25. https://doi.org/10.1523/JNEUROSCI.0017-17.2017

    Article  CAS  Google Scholar 

  49. Fiacco TA, McCarthy KD (2018) Multiple lines of evidence indicate that gliotransmission does not occur under physiological conditions. J Neurosci 38:3–13. https://doi.org/10.1523/JNEUROSCI.0016-17.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bazargani N, Attwell D (2016) Astrocyte calcium signaling: the third wave. Nat Neurosci 19:182–189. https://doi.org/10.1038/nn.4201

    Article  CAS  PubMed  Google Scholar 

  51. Pasti L, Volterra A, Pozzan T, Carmignoto G (1997) Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J Neurosci 17:7817–7830. https://doi.org/10.1523/JNEUROSCI.17-20-07817.1997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kato D, Eto K, Nabekura J, Wake H (2018) Activity-dependent functions of non-electrical glial cells. J Biochem (Tokyo) 163:457–464. https://doi.org/10.1093/jb/mvy023

    Article  CAS  Google Scholar 

  53. Hirase H, Qian L, Barthó P, Buzsáki G (2004) Calcium dynamics of cortical astrocytic networks in vivo. PLoS Biol 2:e96. https://doi.org/10.1371/journal.pbio.0020096

    Article  PubMed  PubMed Central  Google Scholar 

  54. Chitnis T, Weiner HL (2017) CNS inflammation and neurodegeneration. J Clin Invest 127:3577–3587. https://doi.org/10.1172/JCI90609

    Article  PubMed  PubMed Central  Google Scholar 

  55. Liddelow SA, Guttenplan KA, Clarke LE et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487. https://doi.org/10.1038/nature21029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gu X-L, Long C-X, Sun L et al (2010) Astrocytic expression of Parkinson’s disease-related A53T alpha-synuclein causes neurodegeneration in mice. Mol Brain 3:12. https://doi.org/10.1186/1756-6606-3-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Michell-Robinson MA, Touil H, Healy LM et al (2015) Roles of microglia in brain development, tissue maintenance and repair. Brain J Neurol 138:1138–1159. https://doi.org/10.1093/brain/awv066

    Article  Google Scholar 

  58. Cunningham CL, Martínez-Cerdeño V, Noctor SC (2013) Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci 33:4216–4233. https://doi.org/10.1523/JNEUROSCI.3441-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Shigemoto-Mogami Y, Hoshikawa K, Goldman JE et al (2014) Microglia enhance neurogenesis and oligodendrogenesis in the early postnatal subventricular zone. J Neurosci 34:2231–2243. https://doi.org/10.1523/JNEUROSCI.1619-13.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mosser C-A, Baptista S, Arnoux I, Audinat E (2017) Microglia in CNS development: shaping the brain for the future. Prog Neurobiol 149–150:1–20. https://doi.org/10.1016/j.pneurobio.2017.01.002

    Article  PubMed  Google Scholar 

  61. Sierra A, Encinas JM, Deudero JJP et al (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7:483–495. https://doi.org/10.1016/j.stem.2010.08.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bilbo S, Stevens B (2017) Microglia: the brain’s first responders. Cerebrum Dana Forum Brain Sci 2017:14–17

    Google Scholar 

  63. Gomez-Nicola D, Perry VH (2015) Microglial dynamics and role in the healthy and diseased brain: a paradigm of functional plasticity. Neurosci Rev J Bringing Neurobiol Neurol Psychiatry 21:169–184. https://doi.org/10.1177/1073858414530512

    Article  CAS  Google Scholar 

  64. Wang CC, Wu CH, Shieh JY et al (1996) Immunohistochemical study of amoeboid microglial cells in fetal rat brain. J Anat 189:567–574

    PubMed  PubMed Central  Google Scholar 

  65. Fernández-Arjona del MM, Grondona JM, Granados-Durán P et al (2017) Microglia morphological categorization in a rat model of neuroinflammation by hierarchical cluster and principal components analysis. Front Cell Neurosci 11:235. https://doi.org/10.3389/fncel.2017.00235

    Article  CAS  Google Scholar 

  66. Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53:1181–1194. https://doi.org/10.1007/s12035-014-9070-5

    Article  CAS  PubMed  Google Scholar 

  67. Ajmone-Cat MA, Mancini M, De Simone R et al (2013) Microglial polarization and plasticity: evidence from organotypic hippocampal slice cultures. Glia 61:1698–1711. https://doi.org/10.1002/glia.22550

    Article  PubMed  Google Scholar 

  68. Ponomarev ED, Maresz K, Tan Y, Dittel BN (2007) CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci Off J Soc Neurosci 27:10714–10721. https://doi.org/10.1523/JNEUROSCI.1922-07.2007

    Article  CAS  Google Scholar 

  69. Ransohoff RM (2016) A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 19:987–991. https://doi.org/10.1038/nn.4338

    Article  CAS  PubMed  Google Scholar 

  70. Crain JM, Nikodemova M, Watters JJ (2013) Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice. J Neurosci Res 91:1143–1151. https://doi.org/10.1002/jnr.23242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hammond TR, Dufort C, Dissing-Olesen L et al (2019) Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity 50:253–271.e6. https://doi.org/10.1016/j.immuni.2018.11.004

    Article  CAS  PubMed  Google Scholar 

  72. Nayak D, Roth TL, McGavern DB (2014) Microglia development and function. Annu Rev Immunol 32:367–402. https://doi.org/10.1146/annurev-immunol-032713-120240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Frade JM, Barde YA (1998) Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 20:35–41. https://doi.org/10.1016/s0896-6273(00)80432-8

    Article  CAS  PubMed  Google Scholar 

  74. He H, Zhou Y, Zhou Y et al (2018) Dexmedetomidine mitigates microglia-mediated neuroinflammation through upregulation of programmed cell death protein 1 in a rat spinal cord injury model. J Neurotrauma 35:2591–2603. https://doi.org/10.1089/neu.2017.5625

    Article  PubMed  Google Scholar 

  75. Ueno M, Fujita Y, Tanaka T et al (2013) Layer V cortical neurons require microglial support for survival during postnatal development. Nat Neurosci 16:543–551. https://doi.org/10.1038/nn.3358

    Article  CAS  PubMed  Google Scholar 

  76. Schafer DP, Stevens B (2015) Microglia function in central nervous system development and plasticity. Cold Spring Harb Perspect Biol 7:a020545. https://doi.org/10.1101/cshperspect.a020545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Parkhurst CN, Yang G, Ninan I et al (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155:1596–1609. https://doi.org/10.1016/j.cell.2013.11.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tay TL, Savage JC, Hui CW et al (2017) Microglia across the lifespan: from origin to function in brain development, plasticity and cognition. J Physiol 595:1929–1945. https://doi.org/10.1113/JP272134

    Article  CAS  PubMed  Google Scholar 

  79. Squarzoni P, Oller G, Hoeffel G et al (2014) Microglia modulate wiring of the embryonic forebrain. Cell Rep 8:1271–1279. https://doi.org/10.1016/j.celrep.2014.07.042

    Article  CAS  PubMed  Google Scholar 

  80. Davalos D, Grutzendler J, Yang G et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758. https://doi.org/10.1038/nn1472

    Article  CAS  PubMed  Google Scholar 

  81. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318. https://doi.org/10.1126/science.1110647

    Article  CAS  PubMed  Google Scholar 

  82. McKenzie IA, Ohayon D, Li H et al (2014) Motor skill learning requires active central myelination. Science 346:318–322. https://doi.org/10.1126/science.1254960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Nave K-A, Werner HB (2014) Myelination of the nervous system: mechanisms and functions. Annu Rev Cell Dev Biol 30:503–533. https://doi.org/10.1146/annurev-cellbio-100913-013101

    Article  CAS  PubMed  Google Scholar 

  84. Simons M, Nave K-A (2016) Oligodendrocytes: myelination and axonal support. Cold Spring Harb Perspect Biol 8:a020479. https://doi.org/10.1101/cshperspect.a020479

    Article  CAS  PubMed Central  Google Scholar 

  85. Peferoen L, Kipp M, Valk P et al (2014) Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology 141:302–313. https://doi.org/10.1111/imm.12163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Giacci MK, Bartlett CA, Smith NM et al (2018) Oligodendroglia are particularly vulnerable to oxidative damage after neurotrauma in vivo. J Neurosci 38:6491–6504. https://doi.org/10.1523/JNEUROSCI.1898-17.2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zeis T, Enz L, Schaeren-Wiemers N (2016) The immunomodulatory oligodendrocyte. Brain Res 1641:139–148. https://doi.org/10.1016/j.brainres.2015.09.021

    Article  CAS  PubMed  Google Scholar 

  88. Ramesh G, Benge S, Pahar B, Philipp MT (2012) A possible role for inflammation in mediating apoptosis of oligodendrocytes as induced by the Lyme disease spirochete Borrelia burgdorferi. J Neuroinflammation 9:72. https://doi.org/10.1186/1742-2094-9-72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Balabanov R, Strand K, Goswami R et al (2007) Interferon-gamma-oligodendrocyte interactions in the regulation of experimental autoimmune encephalomyelitis. J Neurosci Off J Soc Neurosci 27:2013–2024. https://doi.org/10.1523/JNEUROSCI.4689-06.2007

    Article  CAS  Google Scholar 

  90. Smith CM, Cooksey E, Duncan ID (2013) Myelin loss does not lead to axonal degeneration in a long-lived model of chronic demyelination. J Neurosci 33:2718–2727. https://doi.org/10.1523/JNEUROSCI.4627-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Banker GA (1980) Trophic interactions between astroglial cells and hippocampal neurons in culture. Science 209:809–810. https://doi.org/10.1126/science.7403847

    Article  CAS  PubMed  Google Scholar 

  92. Schreiner B, Romanelli E, Liberski P et al (2015) Astrocyte depletion impairs redox homeostasis and triggers neuronal loss in the adult CNS. Cell Rep 12:1377–1384. https://doi.org/10.1016/j.celrep.2015.07.051

    Article  CAS  PubMed  Google Scholar 

  93. Bosson A, Boisseau S, Buisson A et al (2015) Disruption of dopaminergic transmission remodels tripartite synapse morphology and astrocytic calcium activity within substantia nigra pars reticulata. Glia 63:673–683. https://doi.org/10.1002/glia.22777

    Article  PubMed  Google Scholar 

  94. Perea G, Navarrete M, Araque A (2009) Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32:421–431. https://doi.org/10.1016/j.tins.2009.05.001

    Article  CAS  PubMed  Google Scholar 

  95. Yamamizu K, Iwasaki M, Takakubo H et al (2017) In vitro modeling of blood-brain barrier with human iPSC-derived endothelial cells, pericytes, neurons, and astrocytes via notch signaling. Stem Cell Rep 8:634–647. https://doi.org/10.1016/j.stemcr.2017.01.023

    Article  CAS  Google Scholar 

  96. van Deijk A-LF, Camargo N, Timmerman J et al (2017) Astrocyte lipid metabolism is critical for synapse development and function in vivo. Glia 65:670–682. https://doi.org/10.1002/glia.23120

    Article  PubMed  Google Scholar 

  97. Henneberger C, Papouin T, Oliet SHR, Rusakov DA (2010) Long-term potentiation depends on release of d-serine from astrocytes. Nature 463:232–236. https://doi.org/10.1038/nature08673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Catalani A, Sabbatini M, Consoli C et al (2002) Glial fibrillary acidic protein immunoreactive astrocytes in developing rat hippocampus. Mech Ageing Dev 123:481–490

    Article  CAS  PubMed  Google Scholar 

  99. Cao X, Li L-P, Wang Q et al (2013) Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med 19:773–777. https://doi.org/10.1038/nm.3162

    Article  CAS  PubMed  Google Scholar 

  100. Martin-Fernandez M, Jamison S, Robin LM et al (2017) Synapse-specific astrocyte gating of amygdala-related behavior. Nat Neurosci 20:1540–1548. https://doi.org/10.1038/nn.4649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Panatier A, Theodosis DT, Mothet J-P et al (2006) Glia-derived d-serine controls NMDA receptor activity and synaptic memory. Cell 125:775–784. https://doi.org/10.1016/j.cell.2006.02.051

    Article  CAS  PubMed  Google Scholar 

  102. Tan Z, Liu Y, Xi W et al (2017) Glia-derived ATP inversely regulates excitability of pyramidal and CCK-positive neurons. Nat Commun 8:13772. https://doi.org/10.1038/ncomms13772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Krzisch M, Temprana SG, Mongiat LA et al (2015) Pre-existing astrocytes form functional perisynaptic processes on neurons generated in the adult hippocampus. Brain Struct Funct 220:2027–2042. https://doi.org/10.1007/s00429-014-0768-y

    Article  PubMed  Google Scholar 

  104. Sultan S, Li L, Moss J et al (2015) Synaptic integration of adult-born hippocampal neurons is locally controlled by astrocytes. Neuron 88:957–972. https://doi.org/10.1016/j.neuron.2015.10.037

    Article  CAS  PubMed  Google Scholar 

  105. Terrillion CE, Abazyan B, Yang Z et al (2017) DISC1 in astrocytes influences adult neurogenesis and hippocampus-dependent behaviors in mice. Neuropsychopharmacology 42:2242–2251. https://doi.org/10.1038/npp.2017.129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Moss J, Gebara E, Bushong EA et al (2016) Fine processes of nestin-GFP-positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature. Proc Natl Acad Sci USA 113:E2536–2545. https://doi.org/10.1073/pnas.1514652113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Seri B, García-Verdugo JM, McEwen BS, Alvarez-Buylla A (2001) Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci Off J Soc Neurosci 21:7153–7160

    Article  CAS  Google Scholar 

  108. Khakh BS, Sofroniew MV (2015) Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 18:942–952. https://doi.org/10.1038/nn.4043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Srinivasan R, Huang BS, Venugopal S et al (2015) Ca2+ signaling in astrocytes from IP3R2−/− mice in brain slices and during startle responses in vivo. Nat Neurosci 18:708–717. https://doi.org/10.1038/nn.4001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Di Castro MA, Chuquet J, Liaudet N et al (2011) Local Ca2+ detection and modulation of synaptic release by astrocytes. Nat Neurosci 14:1276–1284. https://doi.org/10.1038/nn.2929

    Article  CAS  PubMed  Google Scholar 

  111. Osipova ED, Semyachkina-Glushkovskaya OV, Morgun AV et al (2018) Gliotransmitters and cytokines in the control of blood–brain barrier permeability. Rev Neurosci. https://doi.org/10.1515/revneuro-2017-0092

    Article  PubMed  Google Scholar 

  112. Volterra A, Liaudet N, Savtchouk I (2014) Astrocyte Ca2+ signalling: an unexpected complexity. Nat Rev Neurosci 15:327–335. https://doi.org/10.1038/nrn3725

    Article  CAS  PubMed  Google Scholar 

  113. Perea G, Gómez R, Mederos S et al (2016) Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks. Elife 5:e20362. https://doi.org/10.7554/eLife.20362

    Article  PubMed  PubMed Central  Google Scholar 

  114. Covelo A, Araque A (2018) Neuronal activity determines distinct gliotransmitter release from a single astrocyte. Elife 7:e32237. https://doi.org/10.7554/eLife.32237

    Article  PubMed  PubMed Central  Google Scholar 

  115. Shannak K, Rajput A, Rozdilsky B et al (1994) Noradrenaline, dopamine and serotonin levels and metabolism in the human hypothalamus: observations in Parkinson’s disease and normal subjects. Brain Res 639:33–41. https://doi.org/10.1016/0006-8993(94)91761-2

    Article  CAS  PubMed  Google Scholar 

  116. Benskey MJ, Perez RG, Manfredsson FP (2016) The contribution of alpha synuclein to neuronal survival and function—implications for Parkinson’s disease. J Neurochem 137:331–359. https://doi.org/10.1111/jnc.13570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mahul-Mellier A-L, Burtscher J, Maharjan N et al (2020) The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration. Proc Natl Acad Sci 117:4971–4982. https://doi.org/10.1073/pnas.1913904117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Dickson DW, Braak H, Duda JE et al (2009) Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol 8:1150–1157. https://doi.org/10.1016/S1474-4422(09)70238-8

    Article  CAS  PubMed  Google Scholar 

  119. DeMaagd G, Philip A (2015) Parkinson’s disease and its management. Pharm Ther 40:504–532

    Google Scholar 

  120. Subramaniam SR, Vergnes L, Franich NR et al (2014) Region specific mitochondrial impairment in mice with widespread overexpression of alpha-synuclein. Neurobiol Dis 70:204–213. https://doi.org/10.1016/j.nbd.2014.06.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ammal Kaidery N, Thomas B (2018) Current perspective of mitochondrial biology in Parkinson’s disease. Neurochem Int. https://doi.org/10.1016/j.neuint.2018.03.001

    Article  PubMed  Google Scholar 

  122. Monti DA, Zabrecky G, Kremens D et al (2016) N-Acetyl cysteine may support dopamine neurons in Parkinson’s disease: preliminary clinical and cell line data. PLoS ONE 11:e0157602. https://doi.org/10.1371/journal.pone.0157602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Smith KM, Eyal E, Weintraub D, Investigators ADAGIO (2015) Combined rasagiline and antidepressant use in Parkinson disease in the ADAGIO study: effects on nonmotor symptoms and tolerability. JAMA Neurol 72:88–95. https://doi.org/10.1001/jamaneurol.2014.2472

    Article  PubMed  Google Scholar 

  124. Ahuja M, Ammal Kaidery N, Yang L et al (2016) Distinct Nrf2 signaling mechanisms of fumaric acid esters and their role in neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced experimental Parkinson’s-like disease. J Neurosci Off J Soc Neurosci 36:6332–6351. https://doi.org/10.1523/JNEUROSCI.0426-16.2016

    Article  CAS  Google Scholar 

  125. Xu H, Wang Y, Song N et al (2018) New progress on the role of glia in iron metabolism and iron-induced degeneration of dopamine neurons in Parkinson’s disease. Front Mol Neurosci 10:455. https://doi.org/10.3389/fnmol.2017.00455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Rappold PM, Tieu K (2010) Astrocytes and therapeutics for Parkinson’s disease. Neurotherapeutics 7:413–423. https://doi.org/10.1016/j.nurt.2010.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Rocha SM, Cristovão AC, Campos FL et al (2012) Astrocyte-derived GDNF is a potent inhibitor of microglial activation. Neurobiol Dis 47:407–415. https://doi.org/10.1016/j.nbd.2012.04.014

    Article  CAS  PubMed  Google Scholar 

  128. Datta I, Ganapathy K, Razdan R, Bhonde R (2017) Location and number of astrocytes determine dopaminergic neuron survival and function under 6-OHDA stress mediated through differential BDNF release. Mol Neurobiol 1–21:5505. https://doi.org/10.1007/s12035-017-0767-0

    Article  CAS  Google Scholar 

  129. Safi R, Gardaneh M, Panahi Y et al (2012) Optimized quantities of GDNF overexpressed by engineered astrocytes are critical for protection of neuroblastoma cells against 6-OHDA toxicity. J Mol Neurosci MN 46:654–665. https://doi.org/10.1007/s12031-011-9654-8

    Article  CAS  PubMed  Google Scholar 

  130. Renko J-M, Bäck S, Voutilainen MH et al (2018) Mesencephalic astrocyte-derived neurotrophic factor (MANF) elevates stimulus-evoked release of dopamine in freely-moving rats. Mol Neurobiol. https://doi.org/10.1007/s12035-018-0872-8

    Article  PubMed  PubMed Central  Google Scholar 

  131. Hao F, Yang C, Chen S-S et al (2017) Long-term protective effects of AAV9-mesencephalic astrocyte-derived neurotrophic factor gene transfer in Parkinsonian rats. Exp Neurol 291:120–133. https://doi.org/10.1016/j.expneurol.2017.01.008

    Article  CAS  PubMed  Google Scholar 

  132. Zhang J, Cai Q, Jiang M et al (2017) Mesencephalic astrocyte-derived neurotrophic factor alleviated 6-OHDA-induced cell damage via ROS-AMPK/mTOR mediated autophagic inhibition. Exp Gerontol 89:45–56. https://doi.org/10.1016/j.exger.2017.01.010

    Article  CAS  PubMed  Google Scholar 

  133. Miyazaki I, Murakami S, Torigoe N et al (2016) Neuroprotective effects of levetiracetam target xCT in astrocytes in Parkinsonian mice. J Neurochem 136:194–204. https://doi.org/10.1111/jnc.13405

    Article  PubMed  Google Scholar 

  134. Zhang Z, Shen Y, Luo H et al (2018) MANF protects dopamine neurons and locomotion defects from a human α-synuclein induced Parkinson’s disease model in C. elegans by regulating ER stress and autophagy pathways. Exp Neurol 308:59–71. https://doi.org/10.1016/j.expneurol.2018.06.016

    Article  CAS  PubMed  Google Scholar 

  135. Ding YM, Jaumotte JD, Signore AP, Zigmond MJ (2004) Effects of 6-hydroxydopamine on primary cultures of substantia nigra: specific damage to dopamine neurons and the impact of glial cell line-derived neurotrophic factor. J Neurochem 89:776–787. https://doi.org/10.1111/j.1471-4159.2004.02415.x

    Article  CAS  PubMed  Google Scholar 

  136. Le W, Wu J, Tang Y (2016) Protective microglia and their regulation in Parkinson’s disease. Front Mol Neurosci 9:89. https://doi.org/10.3389/fnmol.2016.00089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Nam JH, Leem E, Jeon M-T et al (2015) Induction of GDNF and BDNF by hRheb(S16H) transduction of SNpc neurons: neuroprotective mechanisms of hRheb(S16H) in a model of Parkinson’s disease. Mol Neurobiol 51:487–499. https://doi.org/10.1007/s12035-014-8729-2

    Article  CAS  PubMed  Google Scholar 

  138. Schwartz M, Kipnis J (2004) A common vaccine for fighting neurodegenerative disorders: recharging immunity for homeostasis. Trends Pharmacol Sci 25:407–412. https://doi.org/10.1016/j.tips.2004.06.010

    Article  CAS  PubMed  Google Scholar 

  139. Schwartz M, Ziv Y (2008) Immunity to self and self-maintenance: a unified theory of brain pathologies. Trends Immunol 29:211–219. https://doi.org/10.1016/j.it.2008.01.003

    Article  CAS  PubMed  Google Scholar 

  140. Block ML, Zecca L, Hong J-S (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69. https://doi.org/10.1038/nrn2038

    Article  CAS  PubMed  Google Scholar 

  141. Dufek M, Rektorova I, Thon V et al (2015) Interleukin-6 may contribute to mortality in Parkinson’s disease patients: a 4-year prospective study. Park Dis 2015:898192. https://doi.org/10.1155/2015/898192

    Article  CAS  Google Scholar 

  142. Carta AR, Frau L, Pisanu A et al (2011) Rosiglitazone decreases peroxisome proliferator receptor-γ levels in microglia and inhibits TNF-α production: new evidences on neuroprotection in a progressive Parkinson’s disease model. Neuroscience 194:250–261. https://doi.org/10.1016/j.neuroscience.2011.07.046

    Article  CAS  PubMed  Google Scholar 

  143. Subramaniam SR, Federoff HJ (2017) Targeting microglial activation states as a therapeutic avenue in Parkinson’s disease. Front Aging Neurosci 9:176. https://doi.org/10.3389/fnagi.2017.00176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. McCoy MK, Ruhn KA, Martinez TN et al (2008) Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats. Mol Ther J Am Soc Gene Ther 16:1572–1579. https://doi.org/10.1038/mt.2008.146

    Article  CAS  Google Scholar 

  145. Dehmer T, Heneka MT, Sastre M et al (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 88:494–501

    Article  CAS  PubMed  Google Scholar 

  146. 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 Off Publ Fed Am Soc Exp Biol 19:533–542. https://doi.org/10.1096/fj.04-2751com

    Article  CAS  Google Scholar 

  147. Colombo E, Farina C (2016) Astrocytes: key regulators of neuroinflammation. Trends Immunol 37:608–620. https://doi.org/10.1016/j.it.2016.06.006

    Article  CAS  PubMed  Google Scholar 

  148. Mohsenzadegan M, Fayazi MR, Abdolmaleki M et al (2015) Direct immunomodulatory influence of IFN-β on human astrocytoma cells. Immunopharmacol Immunotoxicol 37:214–219. https://doi.org/10.3109/08923973.2015.1014559

    Article  CAS  PubMed  Google Scholar 

  149. Lecca D, Janda E, Mulas G et al (2018) Boosting phagocytosis and anti-inflammatory phenotype in microglia mediates neuroprotection by PPARγ agonist MDG548 in Parkinson’s disease models. Br J Pharmacol 175:3298–3314. https://doi.org/10.1111/bph.14214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. 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:e8784. https://doi.org/10.1371/journal.pone.0008784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Zhang W, Phillips K, Wielgus AR et al (2011) Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson’s disease. Neurotox Res 19:63–72. https://doi.org/10.1007/s12640-009-9140-z

    Article  CAS  PubMed  Google Scholar 

  152. Jeon H, Kim J-H, Kim J-H et al (2012) Plasminogen activator inhibitor type 1 regulates microglial motility and phagocytic activity. J Neuroinflammation 9:149. https://doi.org/10.1186/1742-2094-9-149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Jo M, Kim J-H, Song GJ et al (2017) Astrocytic orosomucoid-2 modulates microglial activation and neuroinflammation. J Neurosci Off J Soc Neurosci 37:2878–2894. https://doi.org/10.1523/JNEUROSCI.2534-16.2017

    Article  CAS  Google Scholar 

  154. Hoshi A, Tsunoda A, Tada M et al (2017) Expression of aquaporin 1 and aquaporin 4 in the temporal neocortex of patients with Parkinson’s disease. Brain Pathol 27:160–168. https://doi.org/10.1111/bpa.12369

    Article  CAS  PubMed  Google Scholar 

  155. Sun H, Liang R, Yang B et al (2016) Aquaporin-4 mediates communication between astrocyte and microglia: implications of neuroinflammation in experimental Parkinson’s disease. Neuroscience 317:65–75. https://doi.org/10.1016/j.neuroscience.2016.01.003

    Article  CAS  PubMed  Google Scholar 

  156. Mohn TC, Koob AO (2015) Adult Astrogenesis and the etiology of cortical neurodegeneration. J Exp Neurosci 9:25–34. https://doi.org/10.4137/JEN.S25520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647. https://doi.org/10.1016/j.tins.2009.08.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Sofroniew MV (2015) Astrogliosis. Cold Spring Harb Perspect Biol 7:a020420. https://doi.org/10.1101/cshperspect.a020420

    Article  CAS  PubMed Central  Google Scholar 

  159. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol (Berl) 119:7–35. https://doi.org/10.1007/s00401-009-0619-8

    Article  Google Scholar 

  160. Yun SP, Kam T-I, Panicker N et al (2018) Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med 24:931–938. https://doi.org/10.1038/s41591-018-0051-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Kuter K, Olech Ł, Głowacka U (2017) Prolonged dysfunction of astrocytes and activation of microglia accelerate degeneration of dopaminergic neurons in the rat substantia nigra and block compensation of early motor dysfunction induced by 6-OHDA. Mol Neurobiol. https://doi.org/10.1007/s12035-017-0529-z

    Article  PubMed  PubMed Central  Google Scholar 

  162. Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR (2015) Oxidative stress and Parkinson’s disease. Front Neuroanat 9:551. https://doi.org/10.3389/fnana.2015.00091

    Article  CAS  Google Scholar 

  163. Bhattacharjee N, Borah A (2016) Oxidative stress and mitochondrial dysfunction are the underlying events of dopaminergic neurodegeneration in homocysteine rat model of Parkinson’s disease. Neurochem Int 101:48–55. https://doi.org/10.1016/j.neuint.2016.10.001

    Article  CAS  PubMed  Google Scholar 

  164. Chen P-C, Vargas MR, Pani AK et al (2009) Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: critical role for the astrocyte. Proc Natl Acad Sci USA 106:2933–2938. https://doi.org/10.1073/pnas.0813361106

    Article  PubMed  PubMed Central  Google Scholar 

  165. Gan L, Vargas MR, Johnson DA, Johnson JA (2012) Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synuclein mutant (A53T) mouse model. J Neurosci Off J Soc Neurosci 32:17775–17787. https://doi.org/10.1523/JNEUROSCI.3049-12.2012

    Article  CAS  Google Scholar 

  166. Jakel RJ, Townsend JA, Kraft AD, Johnson JA (2007) Nrf2-mediated protection against 6-hydroxydopamine. Brain Res 1144:192–201. https://doi.org/10.1016/j.brainres.2007.01.131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Liddell JR (2017) Are astrocytes the predominant cell type for activation of Nrf2 in aging and neurodegeneration? Antioxid Basel Switz 6:65. https://doi.org/10.3390/antiox6030065

    Article  CAS  Google Scholar 

  168. Mallajosyula JK, Kaur D, Chinta SJ et al (2008) MAO-B elevation in mouse brain astrocytes results in Parkinson’s pathology. PLoS ONE 3:e1616. https://doi.org/10.1371/journal.pone.0001616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Finberg JPM, Rabey JM (2016) Inhibitors of MAO-A and MAO-B in psychiatry and neurology. Front Pharmacol 7:340. https://doi.org/10.3389/fphar.2016.00340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Graves SM, Xie Z, Stout KA et al (2020) Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain. Nat Neurosci 23:15–20. https://doi.org/10.1038/s41593-019-0556-3

    Article  CAS  PubMed  Google Scholar 

  171. Guo X, Jiang Q, Tuccitto A et al (2018) The AMPK-PGC-1α signaling axis regulates the astrocyte glutathione system to protect against oxidative and metabolic injury. Neurobiol Dis 113:59–69. https://doi.org/10.1016/j.nbd.2018.02.004

    Article  CAS  PubMed  Google Scholar 

  172. Tong J, Rathitharan G, Meyer JH et al (2017) Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders. Brain 140:2460–2474. https://doi.org/10.1093/brain/awx172

    Article  PubMed  PubMed Central  Google Scholar 

  173. Chan HH, Tse MK, Kumar S, Zhuo L (2018) A novel selective MAO-B inhibitor with neuroprotective and anti-Parkinsonian properties. Eur J Pharmacol 818:254–262. https://doi.org/10.1016/j.ejphar.2017.10.023

    Article  CAS  PubMed  Google Scholar 

  174. Qian L, Tan KS, Wei S-J et al (1950) (2007) Microglia-mediated neurotoxicity is inhibited by morphine through an opioid receptor-independent reduction of NADPH oxidase activity. J Immunol Baltim Md 179:1198–1209

    Google Scholar 

  175. Gao H-M, Liu B, Zhang W, Hong J-S (2003) Critical role of microglial NADPH oxidase-derived free radicals in the in vitro MPTP model of Parkinson’s disease. FASEB J Off Publ Fed Am Soc Exp Biol 17:1954–1956. https://doi.org/10.1096/fj.03-0109fje

    Article  CAS  Google Scholar 

  176. Koyano F, Matsuda N (2015) Molecular mechanisms underlying PINK1 and Parkin catalyzed ubiquitylation of substrates on damaged mitochondria. Biochim Biophys Acta BBA Mol Cell Res 1853:2791–2796. https://doi.org/10.1016/j.bbamcr.2015.02.009

    Article  CAS  Google Scholar 

  177. Kitada T, Asakawa S, Hattori N et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608. https://doi.org/10.1038/33416

    Article  CAS  PubMed  Google Scholar 

  178. Lücking CB, Dürr A, Bonifati V et al (2000) Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 342:1560–1567. https://doi.org/10.1056/NEJM200005253422103

    Article  PubMed  Google Scholar 

  179. Booth HDE, Hirst WD, Wade-Martins R (2017) The role of astrocyte dysfunction in Parkinson’s disease pathogenesis. Trends Neurosci 40:358–370. https://doi.org/10.1016/j.tins.2017.04.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Solano RM, Casarejos MJ, Menéndez-Cuervo J et al (2008) Glial dysfunction in parkin null mice: effects of aging. J Neurosci Off J Soc Neurosci 28:598–611. https://doi.org/10.1523/JNEUROSCI.4609-07.2008

    Article  CAS  Google Scholar 

  181. Solano RM, Menéndez J, Casarejos MJ et al (2006) Midbrain neuronal cultures from parkin mutant mice are resistant to nitric oxide-induced toxicity. Neuropharmacology 51:327–340. https://doi.org/10.1016/j.neuropharm.2006.03.027

    Article  CAS  PubMed  Google Scholar 

  182. Giguere N, Pacelli C, Saumure C et al (2018) Comparative analysis of Parkinson’s disease-associated genes reveals altered survival and bioenergetics of parkin-deficient dopamine neurons in mice. J Biol Chem 293(25):9580–9593. https://doi.org/10.1074/jbc.RA117.000499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Dionísio PEA, Oliveira SR, Amaral JSJD, Rodrigues CMP (2019) Loss of microglial parkin inhibits necroptosis and contributes to neuroinflammation. Mol Neurobiol 56:2990–3004. https://doi.org/10.1007/s12035-018-1264-9

    Article  CAS  PubMed  Google Scholar 

  184. Tran TA, Nguyen AD, Chang J et al (2011) Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B. PLoS ONE 6:e23660. https://doi.org/10.1371/journal.pone.0023660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Shendelman S, Jonason A, Martinat C et al (2004) DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol 2:e362. https://doi.org/10.1371/journal.pbio.0020362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Gorshkov K, Aguisanda F, Thorne N, Zheng W (2018) Astrocytes as targets for drug discovery. Drug Discov Today. https://doi.org/10.1016/j.drudis.2018.01.011

    Article  PubMed  PubMed Central  Google Scholar 

  187. Mullett SJ, Hinkle DA (2011) DJ-1 deficiency in astrocytes selectively enhances mitochondrial complex I inhibitor-induced neurotoxicity. J Neurochem 117:375–387. https://doi.org/10.1111/j.1471-4159.2011.07175.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Mullett SJ, Di Maio R, Greenamyre JT, Hinkle DA (2013) DJ-1 expression modulates astrocyte-mediated protection against neuronal oxidative stress. J Mol Neurosci MN 49:507–511. https://doi.org/10.1007/s12031-012-9904-4

    Article  CAS  PubMed  Google Scholar 

  189. Lev N, Barhum Y, Ben-Zur T et al (2013) Knocking out DJ-1 attenuates astrocytes neuroprotection against 6-hydroxydopamine toxicity. J Mol Neurosci MN 50:542–550. https://doi.org/10.1007/s12031-013-9984-9

    Article  CAS  PubMed  Google Scholar 

  190. Mullett SJ, Hinkle DA (2009) DJ-1 knock-down in astrocytes impairs astrocyte-mediated neuroprotection against rotenone. Neurobiol Dis 33:28–36. https://doi.org/10.1016/j.nbd.2008.09.013

    Article  PubMed  Google Scholar 

  191. Kim J, Choi D, Jeong H et al (2013) 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 60:1–10. https://doi.org/10.1016/j.nbd.2013.08.007

    Article  CAS  PubMed  Google Scholar 

  192. Kim J-M, Cha S-H, Choi YR et al (2016) DJ-1 deficiency impairs glutamate uptake into astrocytes via the regulation of flotillin-1 and caveolin-1 expression. Sci Rep 6:28823. https://doi.org/10.1038/srep28823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Kim KS, Kim JS, Park J-Y et al (2013) DJ-1 associates with lipid rafts by palmitoylation and regulates lipid rafts-dependent endocytosis in astrocytes. Hum Mol Genet 22:4805–4817. https://doi.org/10.1093/hmg/ddt332

    Article  CAS  PubMed  Google Scholar 

  194. Simons K, Toomre D (2000) Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1:31–39. https://doi.org/10.1038/35036052

    Article  CAS  PubMed  Google Scholar 

  195. Fabelo N, Martín V, Santpere G et al (2011) Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson’s disease and incidental Parkinson’s disease. Mol Med 17:1107–1118. https://doi.org/10.2119/molmed.2011.00119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Fallon L, Moreau F, Croft BG et al (2002) Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain. J Biol Chem 277:486–491. https://doi.org/10.1074/jbc.M109806200

    Article  CAS  PubMed  Google Scholar 

  197. Silvestri L, Caputo V, Bellacchio E et al (2005) Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet 14:3477–3492. https://doi.org/10.1093/hmg/ddi377

    Article  CAS  PubMed  Google Scholar 

  198. Fortin DL, Troyer MD, Nakamura K et al (2004) Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci Off J Soc Neurosci 24:6715–6723. https://doi.org/10.1523/JNEUROSCI.1594-04.2004

    Article  CAS  Google Scholar 

  199. Frøyset AK, Edson AJ, Gharbi N et al (2018) Astroglial DJ-1 over-expression up-regulates proteins involved in redox regulation and is neuroprotective in vivo. Redox Biol 16:237–247. https://doi.org/10.1016/j.redox.2018.02.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Zimprich A, Biskup S, Leitner P et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607. https://doi.org/10.1016/j.neuron.2004.11.005

    Article  CAS  PubMed  Google Scholar 

  201. Simón-Sánchez J, Schulte C, Bras JM et al (2009) Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 41:1308–1312. https://doi.org/10.1038/ng.487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Moehle MS, Webber PJ, Tse T et al (2012) LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci 32:1602–1611. https://doi.org/10.1523/JNEUROSCI.5601-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Schapansky J, Nardozzi JD, Felizia F, LaVoie MJ (2014) Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy. Hum Mol Genet 23:4201–4214. https://doi.org/10.1093/hmg/ddu138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Games D, Seubert P, Rockenstein E et al (2013) Axonopathy in an α-synuclein transgenic model of Lewy body disease is associated with extensive accumulation of C-terminal—truncated α-synuclein. Am J Pathol 182:940–953. https://doi.org/10.1016/j.ajpath.2012.11.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Russo I, Kaganovich A, Ding J et al (2019) Transcriptome analysis of LRRK2 knock-out microglia cells reveals alterations of inflammatory- and oxidative stress-related pathways upon treatment with α-synuclein fibrils. Neurobiol Dis 129:67–78. https://doi.org/10.1016/j.nbd.2019.05.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Henry AG, Aghamohammadzadeh S, Samaroo H et al (2015) Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression. Hum Mol Genet 24:6013–6028. https://doi.org/10.1093/hmg/ddv314

    Article  CAS  PubMed  Google Scholar 

  207. Chen X, Liu Z, Cao B-B et al (2017) TGF-β1 Neuroprotection via inhibition of microglial activation in a rat model of Parkinson’s disease. J Neuroimmune Pharmacol 12:433–446. https://doi.org/10.1007/s11481-017-9732-y

    Article  PubMed  Google Scholar 

  208. Oh SH, Kim HN, Park HJ et al (2017) The cleavage effect of mesenchymal stem cell and its derived matrix metalloproteinase-2 on extracellular α-synuclein aggregates in Parkinsonian models. Stem Cells Transl Med 6:949–961. https://doi.org/10.5966/sctm.2016-0111

    Article  CAS  PubMed  Google Scholar 

  209. Booth HDE, Wessely F, Connor-Robson N et al (2019) RNA sequencing reveals MMP2 and TGFB1 downregulation in LRRK2 G2019S Parkinson’s iPSC-derived astrocytes. Neurobiol Dis 129:56–66. https://doi.org/10.1016/j.nbd.2019.05.006

    Article  CAS  PubMed  Google Scholar 

  210. Spillantini MG, Crowther RA, Jakes R et al (1998) Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 95:6469–6473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Spillantini MG, Schmidt ML, Lee VM et al (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840. https://doi.org/10.1038/42166

    Article  CAS  PubMed  Google Scholar 

  212. 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 (Berl) 114:231–241. https://doi.org/10.1007/s00401-007-0244-3

    Article  CAS  Google Scholar 

  213. Cavaliere F, Cerf L, Dehay B et al (2017) In vitro α-synuclein neurotoxicity and spreading among neurons and astrocytes using Lewy body extracts from Parkinson disease brains. Neurobiol Dis 103:101–112. https://doi.org/10.1016/j.nbd.2017.04.011

    Article  CAS  PubMed  Google Scholar 

  214. Reyes JF, Olsson TT, Lamberts JT et al (2015) A cell culture model for monitoring α-synuclein cell-to-cell transfer. Neurobiol Dis 77:266–275. https://doi.org/10.1016/j.nbd.2014.07.003

    Article  CAS  PubMed  Google Scholar 

  215. Lindström V, Gustafsson G, Sanders LH et al (2017) Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage. Mol Cell Neurosci 82:143–156. https://doi.org/10.1016/j.mcn.2017.04.009

    Article  CAS  PubMed  Google Scholar 

  216. Chavarría C, Rodríguez-Bottero S, Quijano C et al (2018) Impact of monomeric, oligomeric and fibrillar alpha-synuclein on astrocyte reactivity and toxicity to neurons. Biochem J 475:3153–3169. https://doi.org/10.1042/BCJ20180297

    Article  PubMed  Google Scholar 

  217. Lee H-J, Suk J-E, 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. https://doi.org/10.1074/jbc.M109.081125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Phatnani H, Maniatis T (2015) Astrocytes in neurodegenerative disease. Cold Spring Harb Perspect Biol 7:a020628. https://doi.org/10.1101/cshperspect.a020628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Kim C, Lee H-J, Masliah E, Lee S-J (2016) Non-cell-autonomous neurotoxicity of α-synuclein through microglial toll-like receptor 2. Exp Neurobiol 25:113–119. https://doi.org/10.5607/en.2016.25.3.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Zhang Q-S, Heng Y, Yuan Y-H, Chen N-H (2017) Pathological α-synuclein exacerbates the progression of Parkinson’s disease through microglial activation. Toxicol Lett 265:30–37. https://doi.org/10.1016/j.toxlet.2016.11.002

    Article  CAS  PubMed  Google Scholar 

  221. Paxinou E, Chen Q, Weisse M et al (2001) Induction of alpha-synuclein aggregation by intracellular nitrative insult. J Neurosci Off J Soc Neurosci 21:8053–8061

    Article  CAS  Google Scholar 

  222. Tapias V, Hu X, Luk KC et al (2017) Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via inos-mediated nitric oxide production. Cell Mol Life Sci CMLS 74:2851–2874. https://doi.org/10.1007/s00018-017-2541-x

    Article  CAS  PubMed  Google Scholar 

  223. Olsen AL, Feany MB (2019) Glial α-synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo. Glia 67:1933–1957. https://doi.org/10.1002/glia.23671

    Article  PubMed  PubMed Central  Google Scholar 

  224. Neumann J, Bras J, Deas E et al (2009) Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain J Neurol 132:1783–1794. https://doi.org/10.1093/brain/awp044

    Article  Google Scholar 

  225. Lang C, Campbell KR, Ryan BJ et al (2019) Single-cell sequencing of iPSC-dopamine neurons reconstructs disease progression and identifies HDAC4 as a regulator of Parkinson cell phenotypes. Cell Stem Cell 24:93–106.e6. https://doi.org/10.1016/j.stem.2018.10.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Chao DHM, Kallemeijn WW, Marques ARA et al (2015) Visualization of active glucocerebrosidase in rodent brain with high spatial resolution following in situ labeling with fluorescent activity based probes. PLoS ONE 10:e0138107. https://doi.org/10.1371/journal.pone.0138107

    Article  CAS  Google Scholar 

  227. Sanyal A, DeAndrade MP, Novis HS et al (2020) Lysosome and inflammatory defects in GBA1-mutant astrocytes are normalized by LRRK2 inhibition. Mov Disord Off J Mov Disord Soc. https://doi.org/10.1002/mds.27994

    Article  Google Scholar 

  228. Osellame LD, Duchen MR (2013) Defective quality control mechanisms and accumulation of damaged mitochondria link Gaucher and Parkinson diseases. Autophagy 9:1633–1635. https://doi.org/10.4161/auto.25878

    Article  CAS  PubMed  Google Scholar 

  229. Li X, Tao Y, Bradley R et al (2018) Fast generation of functional subtype astrocytes from human pluripotent stem cells. Stem Cell Rep 11:998–1008. https://doi.org/10.1016/j.stemcr.2018.08.019

    Article  CAS  Google Scholar 

  230. Santos R, Vadodaria KC, Jaeger BN et al (2017) Differentiation of inflammation-responsive astrocytes from glial progenitors generated from human induced pluripotent stem cells. Stem Cell Rep 8:1757–1769. https://doi.org/10.1016/j.stemcr.2017.05.011

    Article  CAS  Google Scholar 

  231. Jones VC, Atkinson-Dell R, Verkhratsky A, Mohamet L (2017) Aberrant iPSC-derived human astrocytes in Alzheimer’s disease. Cell Death Dis 8:e2696. https://doi.org/10.1038/cddis.2017.89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Krencik R, Zhang S-C (2011) Directed differentiation of functional astroglial subtypes from human pluripotent stem cells. Nat Protoc 6:1710–1717. https://doi.org/10.1038/nprot.2011.405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. di Domenico A, Carola G, Calatayud C et al (2019) Patient-specific iPSC-derived astrocytes contribute to non-cell-autonomous neurodegeneration in Parkinson’s disease. Stem Cell Rep 12:213–229. https://doi.org/10.1016/j.stemcr.2018.12.011

    Article  CAS  Google Scholar 

  234. Gupta K, Patani R, Baxter P et al (2012) Human embryonic stem cell derived astrocytes mediate non-cell-autonomous neuroprotection through endogenous and drug-induced mechanisms. Cell Death Differ 19:779–787. https://doi.org/10.1038/cdd.2011.154

    Article  CAS  PubMed  Google Scholar 

  235. Thorne N, Malik N, Shah S et al (2016) High-throughput phenotypic screening of human astrocytes to identify compounds that protect against oxidative stress. Stem Cells Transl Med 5:613–627. https://doi.org/10.5966/sctm.2015-0170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Harms AS, Barnum CJ, Ruhn KA et al (2011) Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson’s disease. Mol Ther J Am Soc Gene Ther 19:46–52. https://doi.org/10.1038/mt.2010.217

    Article  CAS  Google Scholar 

  237. Joniec-Maciejak I, Ciesielska A, Wawer A et al (2014) The influence of AAV2-mediated gene transfer of human IL-10 on neurodegeneration and immune response in a murine model of Parkinson’s disease. Pharmacol Rep PR 66:660–669. https://doi.org/10.1016/j.pharep.2014.03.008

    Article  CAS  PubMed  Google Scholar 

  238. Schwenkgrub J, Joniec-Maciejak I, Sznejder-Pachołek A et al (2013) Effect of human interleukin-10 on the expression of nitric oxide synthases in the MPTP-based model of Parkinson’s disease. Pharmacol Rep PR 65:44–49

    Article  CAS  PubMed  Google Scholar 

  239. Garbes L, Riessland M, Wirth B (2013) Histone acetylation as a potential therapeutic target in motor neuron degenerative diseases. Curr Pharm Des 19:5093–5104

    Article  CAS  PubMed  Google Scholar 

  240. Tan Y, Delvaux E, Nolz J et al (2018) Upregulation of histone deacetylase 2 in laser capture nigral microglia in Parkinson’s disease. Neurobiol Aging 68:134–141. https://doi.org/10.1016/j.neurobiolaging.2018.02.018

    Article  CAS  PubMed  Google Scholar 

  241. Faraco G, Pittelli M, Cavone L et al (2009) Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo. Neurobiol Dis 36:269–279. https://doi.org/10.1016/j.nbd.2009.07.019

    Article  CAS  PubMed  Google Scholar 

  242. Cassano T, Calcagnini S, Pace L et al (2017) Cannabinoid receptor 2 signaling in neurodegenerative disorders: from pathogenesis to a promising therapeutic target. Front Neurosci 11:30. https://doi.org/10.3389/fnins.2017.00030

    Article  PubMed  PubMed Central  Google Scholar 

  243. Price DA, Martinez AA, Seillier A et al (2009) WIN55,212–2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the MPTP mouse model of Parkinson’s disease. Eur J Neurosci 29:2177–2186. https://doi.org/10.1111/j.1460-9568.2009.06764.x

    Article  PubMed  PubMed Central  Google Scholar 

  244. White RE, Barry DS (2015) The emerging roles of transplanted radial glial cells in regenerating the central nervous system. Neural Regen Res 10:1548–1551. https://doi.org/10.4103/1673-5374.165317

    Article  PubMed  PubMed Central  Google Scholar 

  245. Jha MK, Seo M, Kim J-H et al (2013) The secretome signature of reactive glial cells and its pathological implications. Biochim Biophys Acta 1834:2418–2428. https://doi.org/10.1016/j.bbapap.2012.12.006

    Article  CAS  PubMed  Google Scholar 

  246. Chang M-Y, Son H, Lee Y-S, Lee S-H (2003) Neurons and astrocytes secrete factors that cause stem cells to differentiate into neurons and astrocytes, respectively. Mol Cell Neurosci 23:414–426

    Article  CAS  PubMed  Google Scholar 

  247. Choi SS, Lee HJ, Lim I et al (2014) Human astrocytes: secretome profiles of cytokines and chemokines. PLoS ONE 9:e92325. https://doi.org/10.1371/journal.pone.0092325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Suk K (2010) Combined analysis of the glia secretome and the CSF proteome: neuroinflammation and novel biomarkers. Expert Rev Proteomics 7:263–274. https://doi.org/10.1586/epr.10.6

    Article  CAS  PubMed  Google Scholar 

  249. Jeon H, Lee S, Lee W-H, Suk K (2010) Analysis of glial secretome: the long pentraxin PTX3 modulates phagocytic activity of microglia. J Neuroimmunol 229:63–72. https://doi.org/10.1016/j.jneuroim.2010.07.001

    Article  CAS  PubMed  Google Scholar 

  250. Karpinar DP, Balija MBG, Kügler S et al (2009) Pre-fibrillar α-synuclein variants with impaired β-structure increase neurotoxicity in Parkinson’s disease models. EMBO J 28:3256–3268. https://doi.org/10.1038/emboj.2009.257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Dehay B, Bezard E (2019) Intrastriatal injection of alpha-synuclein fibrils induces Parkinson-like pathology in macaques. Brain 142:3321–3322. https://doi.org/10.1093/brain/awz329

    Article  PubMed  Google Scholar 

  252. O’Donovan SM, Crowley EK, Brown JR-M et al (2020) Nigral overexpression of α-synuclein in a rat Parkinson’s disease model indicates alterations in the enteric nervous system and the gut microbiome. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc 32:e13726. https://doi.org/10.1111/nmo.13726

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors want to acknowledge the financial support from Prémios Santa Casa Neurociências Prize Mantero Belard for Neurodegenerative Diseases Research (MB-28-2019). This work was supported by the European Regional Development Fund (FEDER), through the Competitiveness Internationalization Operational Programme (POCI), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the projects POCI-01-0145-FEDER-029751, POCI-01-0145-FEDER-007038, UIDB/50026/2020 and UIDP/50026/2020; POCI-01-0145-FEDER-016428 (MEDPERSYST) and PTDC/MED-NEU/29071/2017 (REWSTRESS); and by the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by Norte Portugal Regional Operational Programme (NORTE 2020). AVD has an FCT grant (SFRH/BD/147066/2019).

Author information

Authors and Affiliations

  1. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal

    Ana V. Domingues, Inês M. Pereira, Helena Vilaça-Faria, António J. Salgado, Ana J. Rodrigues & Fábio G. Teixeira

  2. ICVS/3B’s Associate Lab, PT Government Associated Laboratory, Braga/Guimarães, Portugal

    Ana V. Domingues, Inês M. Pereira, Helena Vilaça-Faria, António J. Salgado, Ana J. Rodrigues & Fábio G. Teixeira

Authors
  1. Ana V. Domingues
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Inês M. Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Helena Vilaça-Faria
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. António J. Salgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ana J. Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fábio G. Teixeira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ana J. Rodrigues or Fábio G. Teixeira.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Ana. J. Rodrigues and Fábio G. Teixeira share senior authorship

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Domingues, A.V., Pereira, I.M., Vilaça-Faria, H. et al. Glial cells in Parkinson´s disease: protective or deleterious?. Cell. Mol. Life Sci. 77, 5171–5188 (2020). https://doi.org/10.1007/s00018-020-03584-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-020-03584-x

Keywords

Search

Navigation