| Regulator of G-protein signaling-10 negatively regulates NF-κB in microglia and neuroprotects dopaminergic neurons in hemiparkinsonian rats. | |
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MedLine Citation:
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PMID: 21849548 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Microglia are the brain-resident macrophages responsible for immune surveillance that become activated in response to injury, infection, environmental toxins, and other stimuli that threaten neuronal survival. Previous work from our group demonstrated that mice deficient in Regulator of G-protein Signaling 10 (RGS10), a microglia-enriched GTPase activating protein (GAP) for G-protein α subunits, displayed increased microglial burden in the CNS at birth and developed a parkinsonian phenotype after exposure to chronic systemic inflammation, implicating a neuroprotective role for RGS10 in the nigrostriatal pathway. While it is known that RGS10 is expressed in both microglia and certain subsets of neurons, it is not known whether RGS10 functions similarly in both cells types. In this study we sought to delineate the specific role of RGS10 in microglia and identify the molecular pathway(s) required for RGS10 to exert its actions in microglia. Here, we identify RGS10 as a negative regulator of the nuclear factor κB(NF-κB) pathway in microglia and demonstrate that the proinflammatory and cytotoxic phenotype of Rgs10-null microglia can be reversed by lentiviral-mediated restoration of RGS10 expression. In vivo gene transfer of RGS10 into the substantia nigra pars compacta (SNpc) of rats reduced microgliosis and protected against 6-OHDA neurotoxin-induced death of dopaminergic (DA) neurons. Together, our findings suggest that modulation of RGS10 activity in microglia may afford therapeutic benefit in the treatment of chronic neuroinflammatory conditions as well as neuroprotection against inflammation-related degeneration in Parkinson's disease (PD), the second most common neurodegenerative disorder affecting individuals over age 65. |
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Authors:
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Jae-Kyung Lee; Jaegwon Chung; Fiona E McAlpine; Malú G Tansey |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of neuroscience : the official journal of the Society for Neuroscience Volume: 31 ISSN: 1529-2401 ISO Abbreviation: J. Neurosci. Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-08-18 Completed Date: 2011-10-13 Revised Date: 2012-04-18 |
Medline Journal Info:
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Nlm Unique ID: 8102140 Medline TA: J Neurosci Country: United States |
Other Details:
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Languages: eng Pagination: 11879-88 Citation Subset: IM |
Affiliation:
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Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Cells, Cultured Dopamine / physiology* Down-Regulation / genetics, physiology* Female Humans Lentivirus / genetics Mice Mice, Inbred C57BL Mice, Knockout Microglia / metabolism*, physiology NF-kappa B / antagonists & inhibitors*, biosynthesis, metabolism Neurons / pathology, physiology* Parkinsonian Disorders / pathology, prevention & control* RGS Proteins / physiology* Rats Rats, Sprague-Dawley |
| Grant Support | |
ID/Acronym/Agency:
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R01 NS072467-01/NS/NINDS NIH HHS; R01 NS072467-02/NS/NINDS NIH HHS; R01NS072467-01/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/NF-kappa B; 0/RGS Proteins; 0/Rgs10 protein, mouse |
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