| Autor: |
Maatouk L; Institute of Biology Paris Seine, Team Gene Regulation and Adaptive Behaviors, Department of Neurosciences Paris Seine, Sorbonne Université, CNRS UMR 8246, INSERM U1130, 9 Quai Saint Bernard, F-75005, Paris, France., Yi C; CIRB, UMR CNRS 7241/ INSERM 1050, Collège de France, Paris, France., Carrillo-de Sauvage MA; CEA, DRF, MIRCen, Université Paris-Sud, CNRS UMR 9199, Neurodegenerative Diseases Laboratory, F-92260, Fontenay-aux-Roses, France., Compagnion AC; Institute of Biology Paris Seine, Team Gene Regulation and Adaptive Behaviors, Department of Neurosciences Paris Seine, Sorbonne Université, CNRS UMR 8246, INSERM U1130, 9 Quai Saint Bernard, F-75005, Paris, France., Hunot S; Inserm UMRS 1127, CNRS UMR 7225, Sorbonne Université, Institut du Cerveau et de la Moelle Epinière (ICM), F-75013, Paris, France., Ezan P; CIRB, UMR CNRS 7241/ INSERM 1050, Collège de France, Paris, France., Hirsch EC; Inserm UMRS 1127, CNRS UMR 7225, Sorbonne Université, Institut du Cerveau et de la Moelle Epinière (ICM), F-75013, Paris, France., Koulakoff A; CIRB, UMR CNRS 7241/ INSERM 1050, Collège de France, Paris, France., Pfrieger FW; Institute of Cellular and Integrative Neurosciences, CNRS UPR 3212, University of Strasbourg, Strasbourg, France., Tronche F; Institute of Biology Paris Seine, Team Gene Regulation and Adaptive Behaviors, Department of Neurosciences Paris Seine, Sorbonne Université, CNRS UMR 8246, INSERM U1130, 9 Quai Saint Bernard, F-75005, Paris, France., Leybaert L; Physiology group, Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium., Giaume C; CIRB, UMR CNRS 7241/ INSERM 1050, Collège de France, Paris, France., Vyas S; Institute of Biology Paris Seine, Team Gene Regulation and Adaptive Behaviors, Department of Neurosciences Paris Seine, Sorbonne Université, CNRS UMR 8246, INSERM U1130, 9 Quai Saint Bernard, F-75005, Paris, France. sheela.vyas@upmc.fr. |
| Abstrakt: |
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-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 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 post-mortem 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. |
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