In Vivo Expression of Polyglutamine-Expanded Huntingtin by Mouse Striatal Astrocytes Impairs Glutamate Transport: A Correlation with Huntington's Disease Subjects

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dc.contributor.author Faideau, Mathilde en_US
dc.contributor.author Kim, Jinho en_US
dc.contributor.author Cormier, Kerry en_US
dc.contributor.author Gilmore, Richard en_US
dc.contributor.author Welch, Mackenzie en_US
dc.contributor.author Auregan, Gwennaelle en_US
dc.contributor.author Dufour, Noelle en_US
dc.contributor.author Guillermier, Martine en_US
dc.contributor.author Brouillet, Emmanuel en_US
dc.contributor.author Hantraye, Philippe en_US
dc.contributor.author Déglon, Nicole en_US
dc.contributor.author Ferrante, Robert J. en_US
dc.contributor.author Bonvento, Gilles en_US
dc.date.accessioned 2012-01-09T15:36:58Z
dc.date.available 2012-01-09T15:36:58Z
dc.date.copyright 2010 en_US
dc.date.issued 2010-05-21 en_US
dc.identifier.citation Faideau, Mathilde, Jinho Kim, Kerry Cormier, Richard Gilmore, Mackenzie Welch, Gwennaelle Auregan, Noelle Dufour, Martine Guillermier, Emmanuel Brouillet, Philippe Hantraye, Nicole Déglon, Robert J. Ferrante, Gilles Bonvento. "In Vivo Expression of Polyglutamine-Expanded Huntingtin by Mouse Striatal Astrocytes Impairs Glutamate Transport: A Correlation with Huntington's Disease Subjects" Human Molecular Genetics 19(15): 3053-3067. (2010) en_US
dc.identifier.issn 1460-2083 en_US
dc.identifier.uri http://hdl.handle.net/2144/2825
dc.description.abstract Huntington's disease (HD) is a neurodegenerative disorder previously thought to be of primary neuronal origin, despite ubiquitous expression of mutant huntingtin (mHtt). We tested the hypothesis that mHtt expressed in astrocytes may contribute to the pathogenesis of HD. To better understand the contribution of astrocytes in HD in vivo, we developed a novel mouse model using lentiviral vectors that results in selective expression of mHtt into striatal astrocytes. Astrocytes expressing mHtt developed a progressive phenotype of reactive astrocytes that was characterized by a marked decreased expression of both glutamate transporters, GLAST and GLT-1, and of glutamate uptake. These effects were associated with neuronal dysfunction, as observed by a reduction in DARPP-32 and NR2B expression. Parallel studies in brain samples from HD subjects revealed early glial fibrillary acidic protein expression in striatal astrocytes from Grade 0 HD cases. Astrogliosis was associated with morphological changes that increased with severity of disease, from Grades 0 through 4 and was more prominent in the putamen. Combined immunofluorescence showed co-localization of mHtt in astrocytes in all striatal HD specimens, inclusive of Grade 0 HD. Consistent with the findings from experimental mice, there was a significant grade-dependent decrease in striatal GLT-1 expression from HD subjects. These findings suggest that the presence of mHtt in astrocytes alters glial glutamate transport capacity early in the disease process and may contribute to HD pathogenesis. en_US
dc.description.sponsorship Commissariat à l'énergie atomique et aux énergies alternative; Centre National de la Recherche Scientifique; National Institutes of Health (NS045806, NS058793); United States Veterans Administration; European Community's Seventh Framework Programme (FP7/2007-2013, HEALTH-F5-2008-222925) en_US
dc.language.iso en en_US
dc.publisher Oxford University Press en_US
dc.rights Copyright The Author 2010. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. en_US
dc.rights.uri http://creativecommons.org/licenses/by-nc/2.5/ en_US
dc.title In Vivo Expression of Polyglutamine-Expanded Huntingtin by Mouse Striatal Astrocytes Impairs Glutamate Transport: A Correlation with Huntington's Disease Subjects en_US
dc.type article en_US
dc.identifier.doi 10.1093/hmg/ddq212 en_US
dc.identifier.pubmedid 20494921 en_US
dc.identifier.pmcid 2901144 en_US

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