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

(2019) CELL DEATH AND 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 GR(Cx30CreERT2) 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 GR(Cx30CreERT2) 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-alpha and Il-1 beta as well as TNF-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 MPTP-injected GR(Cx30CreERT2) 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
PARKINSONS-DISEASE, ALPHA-SYNUCLEIN, CX43 HEMICHANNELS, MOUSE MODEL, GENE, MICROGLIA, COMMUNICATION, INFLAMMATION, ACTIVATION, MECHANISMS

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MLA
Maatouk, Layal et al. “Glucocorticoid Receptor in Astrocytes Regulates Midbrain Dopamine Neurodegeneration Through Connexin Hemichannel Activity.” CELL DEATH AND DIFFERENTIATION 26.3 (2019): 580–596. Print.
APA
Maatouk, L., Yi, C., Carrillo-de Sauvage, M.-A., Compagnion, A.-C., Hunot, S., Ezan, P., Hirsch, E. C., et al. (2019). Glucocorticoid receptor in astrocytes regulates midbrain dopamine neurodegeneration through connexin hemichannel activity. CELL DEATH AND DIFFERENTIATION, 26(3), 580–596.
Chicago author-date
Maatouk, Layal, Chenju Yi, Maria-Angeles Carrillo-de Sauvage, Anne-Claire Compagnion, Stéphane Hunot, Pascal Ezan, Etienne C Hirsch, et al. 2019. “Glucocorticoid Receptor in Astrocytes Regulates Midbrain Dopamine Neurodegeneration Through Connexin Hemichannel Activity.” Cell Death and Differentiation 26 (3): 580–596.
Chicago author-date (all authors)
Maatouk, Layal, Chenju Yi, Maria-Angeles Carrillo-de Sauvage, Anne-Claire Compagnion, Stéphane Hunot, Pascal Ezan, Etienne C Hirsch, Annette Koulakoff, Frank W Pfrieger, François Tronche, Luc Leybaert, Christian Giaume, and Sheela Vyas. 2019. “Glucocorticoid Receptor in Astrocytes Regulates Midbrain Dopamine Neurodegeneration Through Connexin Hemichannel Activity.” Cell Death and 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 AND DIFFERENTIATION. 2019;26(3):580–96.
IEEE
[1]
L. Maatouk et al., “Glucocorticoid receptor in astrocytes regulates midbrain dopamine neurodegeneration through connexin hemichannel activity,” CELL DEATH AND DIFFERENTIATION, vol. 26, no. 3, pp. 580–596, 2019.
@article{8607704,
  abstract     = {The precise contribution of astrocytes in neuroinflammatory process occurring in Parkinson's disease (PD) is not well characterized. In this study, using GR(Cx30CreERT2) 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 GR(Cx30CreERT2) 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-alpha and Il-1 beta as well as TNF-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 MPTP-injected GR(Cx30CreERT2) 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, Stéphane and Ezan, Pascal and Hirsch, Etienne C and Koulakoff, Annette and Pfrieger, Frank W and Tronche, François and Leybaert, Luc and Giaume, Christian and Vyas, Sheela},
  issn         = {1350-9047},
  journal      = {CELL DEATH AND DIFFERENTIATION},
  keywords     = {PARKINSONS-DISEASE,ALPHA-SYNUCLEIN,CX43 HEMICHANNELS,MOUSE MODEL,GENE,MICROGLIA,COMMUNICATION,INFLAMMATION,ACTIVATION,MECHANISMS},
  language     = {eng},
  number       = {3},
  pages        = {580--596},
  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         = {2019},
}

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