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Glucocorticoid receptor in astrocytes regulates midbrain dopamine neurodegeneration through connexin hemichannel activity

(2018) Cell Death & Differentiation. 26(3). p.580-596
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Abstract
The precise contribution of astrocytes in neuroinflammatory process occurring in Parkinson’s disease (PD) is not well characterized. In this study, using GRCx30CreERT2 mice that are conditionally inactivated for glucocorticoid receptor (GR) in astrocytes, we have examined the actions of astrocytic GR during dopamine neuron (DN) degeneration triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results show significantly augmented DN loss in GRCx30CreERT2 mutant mice in substantia nigra (SN) compared to controls. Hypertrophy of microglia but not of astrocytes was greatly enhanced in SN of these astrocytic GR mutants intoxicated with MPTP, indicating heightened microglial reactivity compared to similarly-treated control mice. In the SN of GR astrocyte mutants, specific inflammation-associated transcripts ICAM-1, TNF-α and Il-1β as well as TNF-α protein levels were significantly elevated after MPTP neurotoxicity compared to controls. Interestingly, this paralleled increased connexin hemichannel activity and elevated intracellular calcium levels in astrocytes examined in acute midbrain slices from control and mutant mice treated with MPP+ . The increased connexin-43 hemichannel activity was found in vivo in MPTP-intoxicated mice. Importantly, treatment of MPTPinjected GRCx30CreERT2 mutant mice with TAT-Gap19 peptide, a specific connexin-43 hemichannel blocker, reverted both DN loss and microglial activation; in wild-type mice there was partial but significant survival effect. In the SN of postmortem PD patients, a significant decrease in the number of astrocytes expressing nuclear GR was observed, suggesting the participation of astrocytic GR deregulation of inflammatory process in PD. Overall, these data provide mechanistic insights into GR-modulated processes in vivo, specifically in astrocytes, that contribute to a pro-inflammatory state and dopamine neurodegeneration in PD pathology.
Keywords
Cell Biology, Molecular Biology

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Chicago
Maatouk, Layal, Chenju Yi, Maria-Angeles Carrillo-de Sauvage, Anne-Claire Compagnion, Stéphane Hunot, Pascal Ezan, Etienne C. Hirsch, et al. 2018. “Glucocorticoid Receptor in Astrocytes Regulates Midbrain Dopamine Neurodegeneration Through Connexin Hemichannel Activity.” Cell Death & Differentiation 26 (3): 580–596.
APA
Maatouk, L., Yi, C., Carrillo-de Sauvage, M.-A., Compagnion, A.-C., Hunot, S., Ezan, P., Hirsch, E. C., et al. (2018). Glucocorticoid receptor in astrocytes regulates midbrain dopamine neurodegeneration through connexin hemichannel activity. Cell Death & Differentiation, 26(3), 580–596.
Vancouver
1.
Maatouk L, Yi C, Carrillo-de Sauvage M-A, Compagnion A-C, Hunot S, Ezan P, et al. Glucocorticoid receptor in astrocytes regulates midbrain dopamine neurodegeneration through connexin hemichannel activity. Cell Death & Differentiation. Springer Nature; 2018;26(3):580–96.
MLA
Maatouk, Layal et al. “Glucocorticoid Receptor in Astrocytes Regulates Midbrain Dopamine Neurodegeneration Through Connexin Hemichannel Activity.” Cell Death & Differentiation 26.3 (2018): 580–596. Print.
@article{8607704,
  abstract     = {The precise contribution of astrocytes in neuroinflammatory process occurring in Parkinson{\textquoteright}s disease (PD) is not well
characterized. In this study, using GRCx30CreERT2 mice that are conditionally inactivated for glucocorticoid receptor (GR) in
astrocytes, we have examined the actions of astrocytic GR during dopamine neuron (DN) degeneration triggered by the
neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results show significantly augmented DN loss in
GRCx30CreERT2 mutant mice in substantia nigra (SN) compared to controls. Hypertrophy of microglia but not of astrocytes
was greatly enhanced in SN of these astrocytic GR mutants intoxicated with MPTP, indicating heightened microglial
reactivity compared to similarly-treated control mice. In the SN of GR astrocyte mutants, specific inflammation-associated
transcripts ICAM-1, TNF-\ensuremath{\alpha} and Il-1\ensuremath{\beta} as well as TNF-\ensuremath{\alpha} protein levels were significantly elevated after MPTP neurotoxicity
compared to controls. Interestingly, this paralleled increased connexin hemichannel activity and elevated intracellular
calcium levels in astrocytes examined in acute midbrain slices from control and mutant mice treated with MPP+ . The
increased connexin-43 hemichannel activity was found in vivo in MPTP-intoxicated mice. Importantly, treatment of MPTPinjected
GRCx30CreERT2 mutant mice with TAT-Gap19 peptide, a specific connexin-43 hemichannel blocker, reverted both
DN loss and microglial activation; in wild-type mice there was partial but significant survival effect. In the SN of postmortem
PD patients, a significant decrease in the number of astrocytes expressing nuclear GR was observed, suggesting the
participation of astrocytic GR deregulation of inflammatory process in PD. Overall, these data provide mechanistic insights
into GR-modulated processes in vivo, specifically in astrocytes, that contribute to a pro-inflammatory state and dopamine
neurodegeneration in PD pathology.},
  author       = {Maatouk, Layal and Yi, Chenju and Carrillo-de Sauvage, Maria-Angeles and Compagnion, Anne-Claire and Hunot, St{\'e}phane and Ezan, Pascal and Hirsch, Etienne C. and Koulakoff, Annette and Pfrieger, Frank W and Tronche, Fran\c{c}ois and Leybaert, Luc and Giaume, Christian and Vyas, Sheela},
  issn         = {1350-9047},
  journal      = {Cell Death \& Differentiation},
  number       = {3},
  pages        = {580--596},
  publisher    = {Springer Nature},
  title        = {Glucocorticoid receptor in astrocytes regulates midbrain dopamine neurodegeneration through connexin hemichannel activity},
  url          = {http://dx.doi.org/10.1038/s41418-018-0150-3},
  volume       = {26},
  year         = {2018},
}

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