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Nat Commun. 2018 Jun 22;9(1):2450. doi: 10.1038/s41467-018-04569-y.

TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons.

Author information

1
Institute of Biology Paris Seine, Gene Regulation and Adaptive Behaviors Team, Department of Neuroscience Paris Seine, Sorbonne Université, CNRS UMR 8246 & INSERM U1130, 9 Quai Saint Bernard, F-75005, Paris, France.
2
CEA, DRF, Institut François Jacob, Neurodegenerative Diseases Laboratory, Molecular Imaging Research Center (MIRCen), CNRS, CEA, Université Paris-Sud, Université Paris-Saclay (UMR9199), F-92265, Fontenay-aux-Roses, France.
3
IHU-A-ICM-Neuro-CEB, Plateforme de Ressources Biologiques (PRB), Hôpital de la Pitié-Salpétrière, 47 Boulevard de l'Hôpital, F-75013, Paris, France.
4
INEM, INSERM U1151-CNRS UMR 8253, Hôpital Necker, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 149 Rue de Sèvres, F-75005, Paris, France.
5
Institute of Biology Paris Seine, Electron Microscopy Facility, Sorbonne Université FR3631, 9 Quai Saint Bernard, F-75005, Paris, France.
6
Center for Organic Chemistry, Mallinckrodt Pharmaceuticals, 3600N. Second Street, B81-T l, St. Louis, MO, 63147, USA.
7
Third Rock Ventures, Boston, MA, 02116, USA.
8
Institute of Biology Paris Seine, Gene Regulation and Adaptive Behaviors Team, Department of Neuroscience Paris Seine, Sorbonne Université, CNRS UMR 8246 & INSERM U1130, 9 Quai Saint Bernard, F-75005, Paris, France. sheela.vyas@upmc.fr.

Abstract

Inflammation is a characteristic feature of Parkinson's disease (PD). We examined the role of TLR9 and its regulation by glucocorticoid receptors (GRs) in degeneration of substantia nigra dopamine neurons (DNs). TLR9 agonist, CpG-ODN, induced DN degeneration in mice lacking GR in microglia but not in controls. TLR9 deletion reduced DN loss in neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. GR regulates TLR9 activation during MPTP neurotoxicity as TLR9 antagonist suppressed increased DN loss in microglia/macrophage GR mutant mice. GR absence in microglia enhanced TLR9 translocation to endolysosomes and facilitated its cleavage leading to pro-inflammatory gene expression. GR-dependent TLR9 activation also triggered DN loss following intranigral injection of mitochondrial DNA. Finally, microglial GR sensitivity to A53T-alpha-synuclein induced DN degeneration as well as decreased microglial GR expression observed in SN of PD brain samples, all suggest that reduced microglial GR activity in SN can stimulate TLR9 activation and DN loss in PD pathology.

PMID:
29934589
PMCID:
PMC6015079
DOI:
10.1038/s41467-018-04569-y
[Indexed for MEDLINE]
Free PMC Article

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