In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects
Identifieur interne : 001224 ( Istex/Corpus ); précédent : 001223; suivant : 001225In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects
Auteurs : Mathilde Faideau ; Jinho Kim ; Kerry Cormier ; Richard Gilmore ; Mackenzie Welch ; Gwennaelle Auregan ; Noelle Dufour ; Martine Guillermier ; Emmanuel Brouillet ; Philippe Hantraye ; Nicole Dglon ; Robert J. Ferrante ; Gilles BonventoSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-08-01.
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.
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DOI: 10.1093/hmg/ddq212
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and</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</mods:affiliation></affiliation></author><author><name sortKey="Gilmore, Richard" sort="Gilmore, Richard" uniqKey="Gilmore R" first="Richard" last="Gilmore">Richard Gilmore</name><affiliation><mods:affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Laboratory Medicine and Pathology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Laboratory Medicine and Pathology and</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</mods:affiliation></affiliation></author><author><name sortKey="Welch, Mackenzie" sort="Welch, Mackenzie" uniqKey="Welch M" 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France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation></author><author><name sortKey="Dufour, Noelle" sort="Dufour, Noelle" uniqKey="Dufour N" first="Noelle" last="Dufour">Noelle Dufour</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation></author><author><name sortKey="Guillermier, Martine" sort="Guillermier, Martine" uniqKey="Guillermier M" first="Martine" last="Guillermier">Martine Guillermier</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation></author><author><name sortKey="Brouillet, Emmanuel" sort="Brouillet, Emmanuel" uniqKey="Brouillet E" first="Emmanuel" last="Brouillet">Emmanuel Brouillet</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation></author><author><name sortKey="Hantraye, Philippe" sort="Hantraye, Philippe" uniqKey="Hantraye P" first="Philippe" last="Hantraye">Philippe Hantraye</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation></author><author><name sortKey="Dglon, Nicole" sort="Dglon, Nicole" uniqKey="Dglon N" first="Nicole" last="Dglon">Nicole Dglon</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation></author><author><name sortKey="Ferrante, Robert J" sort="Ferrante, Robert J" uniqKey="Ferrante R" first="Robert J." last="Ferrante">Robert J. Ferrante</name><affiliation><mods:affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Laboratory Medicine and Pathology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Laboratory Medicine and Pathology and</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</mods:affiliation></affiliation></author><author><name sortKey="Bonvento, Gilles" sort="Bonvento, Gilles" uniqKey="Bonvento G" first="Gilles" last="Bonvento">Gilles Bonvento</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: gilles.bonvento@cea.fr</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:C34BFFA73C9DE9284564A3AC573DBE243FEF96B8</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1093/hmg/ddq212</idno><idno type="url">https://api.istex.fr/document/C34BFFA73C9DE9284564A3AC573DBE243FEF96B8/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001224</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects</title><author><name sortKey="Faideau, Mathilde" sort="Faideau, Mathilde" uniqKey="Faideau M" first="Mathilde" last="Faideau">Mathilde Faideau</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation></author><author><name sortKey="Kim, Jinho" sort="Kim, Jinho" uniqKey="Kim J" first="Jinho" last="Kim">Jinho Kim</name><affiliation><mods:affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Laboratory Medicine and Pathology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Laboratory Medicine and Pathology and</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</mods:affiliation></affiliation></author><author><name sortKey="Cormier, Kerry" sort="Cormier, Kerry" uniqKey="Cormier K" first="Kerry" last="Cormier">Kerry Cormier</name><affiliation><mods:affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Laboratory Medicine and Pathology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Laboratory Medicine and Pathology and</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</mods:affiliation></affiliation></author><author><name sortKey="Gilmore, Richard" sort="Gilmore, Richard" uniqKey="Gilmore R" first="Richard" last="Gilmore">Richard Gilmore</name><affiliation><mods:affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Laboratory Medicine and Pathology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Laboratory Medicine and Pathology and</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</mods:affiliation></affiliation></author><author><name sortKey="Welch, Mackenzie" sort="Welch, Mackenzie" uniqKey="Welch M" first="Mackenzie" last="Welch">Mackenzie Welch</name><affiliation><mods:affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Laboratory Medicine and Pathology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Laboratory Medicine and Pathology and</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</mods:affiliation></affiliation></author><author><name sortKey="Auregan, Gwennaelle" sort="Auregan, Gwennaelle" uniqKey="Auregan G" first="Gwennaelle" last="Auregan">Gwennaelle Auregan</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation></author><author><name sortKey="Dufour, Noelle" sort="Dufour, Noelle" uniqKey="Dufour N" first="Noelle" last="Dufour">Noelle Dufour</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation></author><author><name sortKey="Guillermier, Martine" sort="Guillermier, Martine" uniqKey="Guillermier M" first="Martine" last="Guillermier">Martine Guillermier</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation></author><author><name sortKey="Brouillet, Emmanuel" sort="Brouillet, Emmanuel" uniqKey="Brouillet E" first="Emmanuel" last="Brouillet">Emmanuel Brouillet</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation></author><author><name sortKey="Hantraye, Philippe" sort="Hantraye, Philippe" uniqKey="Hantraye P" first="Philippe" last="Hantraye">Philippe Hantraye</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation></author><author><name sortKey="Dglon, Nicole" sort="Dglon, Nicole" uniqKey="Dglon N" first="Nicole" last="Dglon">Nicole Dglon</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation></author><author><name sortKey="Ferrante, Robert J" sort="Ferrante, Robert J" uniqKey="Ferrante R" first="Robert J." last="Ferrante">Robert J. Ferrante</name><affiliation><mods:affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Laboratory Medicine and Pathology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Laboratory Medicine and Pathology and</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</mods:affiliation></affiliation></author><author><name sortKey="Bonvento, Gilles" sort="Bonvento, Gilles" uniqKey="Bonvento G" first="Gilles" last="Bonvento">Gilles Bonvento</name><affiliation><mods:affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: gilles.bonvento@cea.fr</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-08-01">2010-08-01</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">15</biblScope><biblScope unit="page" from="3053">3053</biblScope><biblScope unit="page" to="3067">3067</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">C34BFFA73C9DE9284564A3AC573DBE243FEF96B8</idno><idno type="DOI">10.1093/hmg/ddq212</idno><idno type="ArticleID">ddq212</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="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.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Mathilde Faideau</name><affiliations><json:string>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</json:string><json:string>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</json:string></affiliations></json:item><json:item><name>Jinho Kim</name><affiliations><json:string>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</json:string><json:string>Department of Neurology, Laboratory Medicine and Pathology,</json:string><json:string>Department of Laboratory Medicine and Pathology and</json:string><json:string>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</json:string></affiliations></json:item><json:item><name>Kerry Cormier</name><affiliations><json:string>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</json:string><json:string>Department of Neurology, Laboratory Medicine and Pathology,</json:string><json:string>Department of Laboratory Medicine and Pathology and</json:string><json:string>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</json:string></affiliations></json:item><json:item><name>Richard Gilmore</name><affiliations><json:string>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</json:string><json:string>Department of Neurology, Laboratory Medicine and Pathology,</json:string><json:string>Department of Laboratory Medicine and Pathology and</json:string><json:string>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</json:string></affiliations></json:item><json:item><name>Mackenzie Welch</name><affiliations><json:string>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</json:string><json:string>Department of Neurology, Laboratory Medicine and Pathology,</json:string><json:string>Department of Laboratory Medicine and Pathology and</json:string><json:string>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</json:string></affiliations></json:item><json:item><name>Gwennaelle Auregan</name><affiliations><json:string>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</json:string><json:string>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</json:string></affiliations></json:item><json:item><name>Noelle Dufour</name><affiliations><json:string>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</json:string><json:string>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</json:string></affiliations></json:item><json:item><name>Martine Guillermier</name><affiliations><json:string>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</json:string><json:string>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</json:string></affiliations></json:item><json:item><name>Emmanuel Brouillet</name><affiliations><json:string>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</json:string><json:string>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</json:string></affiliations></json:item><json:item><name>Philippe Hantraye</name><affiliations><json:string>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</json:string><json:string>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</json:string></affiliations></json:item><json:item><name>Nicole Dglon</name><affiliations><json:string>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</json:string><json:string>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</json:string></affiliations></json:item><json:item><name>Robert J. Ferrante</name><affiliations><json:string>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</json:string><json:string>Department of Neurology, Laboratory Medicine and Pathology,</json:string><json:string>Department of Laboratory Medicine and Pathology and</json:string><json:string>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</json:string></affiliations></json:item><json:item><name>Gilles Bonvento</name><affiliations><json:string>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</json:string><json:string>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</json:string><json:string>E-mail: gilles.bonvento@cea.fr</json:string></affiliations></json:item></author><articleId><json:string>ddq212</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><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.</abstract><qualityIndicators><score>8.7</score><pdfVersion>1.5</pdfVersion><pdfPageSize>612 x 797.953 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1561</abstractCharCount><pdfWordCount>8494</pdfWordCount><pdfCharCount>54763</pdfCharCount><pdfPageCount>15</pdfPageCount><abstractWordCount>225</abstractWordCount></qualityIndicators><title>In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects</title><genre><json:string>research-article</json:string></genre><host><volume>19</volume><publisherId><json:string>hmg</json:string></publisherId><pages><last>3067</last><first>3053</first></pages><issn><json:string>0964-6906</json:string></issn><issue>15</issue><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2083</json:string></eissn><title>Human Molecular Genetics</title></host><categories><wos><json:string>BIOCHEMISTRY & MOLECULAR BIOLOGY</json:string><json:string>GENETICS & HEREDITY</json:string></wos></categories><publicationDate>2010</publicationDate><copyrightDate>2010</copyrightDate><doi><json:string>10.1093/hmg/ddq212</json:string></doi><id>C34BFFA73C9DE9284564A3AC573DBE243FEF96B8</id><score>0.23370779</score><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/C34BFFA73C9DE9284564A3AC573DBE243FEF96B8/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/C34BFFA73C9DE9284564A3AC573DBE243FEF96B8/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/C34BFFA73C9DE9284564A3AC573DBE243FEF96B8/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects</title><respStmt><resp>Références bibliographiques récupérées via GROBID</resp><name resp="ISTEX-API">ISTEX-API (INIST-CNRS)</name></respStmt></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>The Author 2010. Published by Oxford University Press.</p></availability><date>2010-05-21</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects</title><author xml:id="author-1"><persName><forename type="first">Mathilde</forename><surname>Faideau</surname></persName><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation></author><author xml:id="author-2"><persName><forename type="first">Jinho</forename><surname>Kim</surname></persName><affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</affiliation><affiliation>Department of Neurology, Laboratory Medicine and Pathology,</affiliation><affiliation>Department of Laboratory Medicine and Pathology and</affiliation><affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</affiliation></author><author xml:id="author-3"><persName><forename type="first">Kerry</forename><surname>Cormier</surname></persName><affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</affiliation><affiliation>Department of Neurology, Laboratory Medicine and Pathology,</affiliation><affiliation>Department of Laboratory Medicine and Pathology and</affiliation><affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</affiliation></author><author xml:id="author-4"><persName><forename type="first">Richard</forename><surname>Gilmore</surname></persName><affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</affiliation><affiliation>Department of Neurology, Laboratory Medicine and Pathology,</affiliation><affiliation>Department of Laboratory Medicine and Pathology and</affiliation><affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</affiliation></author><author xml:id="author-5"><persName><forename type="first">Mackenzie</forename><surname>Welch</surname></persName><affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</affiliation><affiliation>Department of Neurology, Laboratory Medicine and Pathology,</affiliation><affiliation>Department of Laboratory Medicine and Pathology and</affiliation><affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</affiliation></author><author xml:id="author-6"><persName><forename type="first">Gwennaelle</forename><surname>Auregan</surname></persName><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation></author><author xml:id="author-7"><persName><forename type="first">Noelle</forename><surname>Dufour</surname></persName><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation></author><author xml:id="author-8"><persName><forename type="first">Martine</forename><surname>Guillermier</surname></persName><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation></author><author xml:id="author-9"><persName><forename type="first">Emmanuel</forename><surname>Brouillet</surname></persName><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation></author><author xml:id="author-10"><persName><forename type="first">Philippe</forename><surname>Hantraye</surname></persName><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation></author><author xml:id="author-11"><persName><forename type="first">Nicole</forename><surname>Dglon</surname></persName><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation></author><author xml:id="author-12"><persName><forename type="first">Robert J.</forename><surname>Ferrante</surname></persName><affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</affiliation><affiliation>Department of Neurology, Laboratory Medicine and Pathology,</affiliation><affiliation>Department of Laboratory Medicine and Pathology and</affiliation><affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</affiliation></author><author xml:id="author-13"><persName><forename type="first">Gilles</forename><surname>Bonvento</surname></persName><email>gilles.bonvento@cea.fr</email><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation></author></analytic><monogr><title level="j">Human Molecular Genetics</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-08-01"></date><biblScope unit="volume">19</biblScope><biblScope unit="issue">15</biblScope><biblScope unit="page" from="3053">3053</biblScope><biblScope unit="page" to="3067">3067</biblScope></imprint></monogr><idno type="istex">C34BFFA73C9DE9284564A3AC573DBE243FEF96B8</idno><idno type="DOI">10.1093/hmg/ddq212</idno><idno type="ArticleID">ddq212</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010-05-21</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>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.</p></abstract></profileDesc><revisionDesc><change when="2010-05-21">Created</change><change when="2010-08-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-10-14">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/C34BFFA73C9DE9284564A3AC573DBE243FEF96B8/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-id journal-id-type="hwp">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/hmg/ddq212</article-id><article-id pub-id-type="publisher-id">ddq212</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title><italic>In vivo</italic> expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Faideau</surname><given-names>Mathilde</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Jinho</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af4">4</xref><xref ref-type="aff" rid="af5">5</xref><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Cormier</surname><given-names>Kerry</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af4">4</xref><xref ref-type="aff" rid="af5">5</xref><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Gilmore</surname><given-names>Richard</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af4">4</xref><xref ref-type="aff" rid="af5">5</xref><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Welch</surname><given-names>Mackenzie</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af4">4</xref><xref ref-type="aff" rid="af5">5</xref><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Auregan</surname><given-names>Gwennaelle</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Dufour</surname><given-names>Noelle</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Guillermier</surname><given-names>Martine</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Brouillet</surname><given-names>Emmanuel</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Hantraye</surname><given-names>Philippe</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Déglon</surname><given-names>Nicole</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ferrante</surname><given-names>Robert J.</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af4">4</xref><xref ref-type="aff" rid="af5">5</xref><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Bonvento</surname><given-names>Gilles</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><institution>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen)</institution>, <addr-line>F-92265 Fontenay-aux-Roses</addr-line>, <country>France</country>,</aff><aff id="af2"><label>2</label><institution>CNRS CEA URA 2210</institution>, <addr-line>F-92265 Fontenay-aux-Roses</addr-line>, <country>France</country>,</aff><aff id="af3"><label>3</label><addr-line>Geriatric Research Education and Clinical Center</addr-line>, <institution>Bedford Veterans Administration Medical Center</institution>, <addr-line>Bedford, MA 01730</addr-line>, <country>USA</country>,</aff><aff id="af4"><label>4</label><addr-line>Department of Neurology</addr-line>, <institution>Laboratory Medicine and Pathology</institution>,</aff><aff id="af5"><label>5</label><addr-line>Department of Laboratory Medicine and Pathology</addr-line> and</aff><aff id="af6"><label>6</label><addr-line>Department of Psychiatry</addr-line>, <institution>Boston University School of Medicine</institution>, <addr-line>Boston, MA 02118</addr-line>, <country>USA</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed. Tel: <phone>+33 146548330</phone>; Fax: <fax>+33 146549116</fax>; Email: <email>gilles.bonvento@cea.fr</email></corresp></author-notes><pub-date pub-type="ppub"><day>1</day><month>8</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>21</day><month>5</month><year>2010</year></pub-date><volume>19</volume><issue>15</issue><fpage>3053</fpage><lpage>3067</lpage><history><date date-type="received"><day>29</day><month>3</month><year>2010</year></date><date date-type="accepted"><day>18</day><month>5</month><year>2010</year></date></history><permissions><copyright-statement>© The Author 2010. Published by Oxford University Press.</copyright-statement><copyright-year>2010</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.5/"><p>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.</p></license></permissions><abstract><p>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 <italic>in vivo</italic>, 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.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects</title></titleInfo><name type="personal"><namePart type="given">Mathilde</namePart><namePart type="family">Faideau</namePart><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jinho</namePart><namePart type="family">Kim</namePart><affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</affiliation><affiliation>Department of Neurology, Laboratory Medicine and Pathology,</affiliation><affiliation>Department of Laboratory Medicine and Pathology and</affiliation><affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kerry</namePart><namePart type="family">Cormier</namePart><affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</affiliation><affiliation>Department of Neurology, Laboratory 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type="family">Welch</namePart><affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</affiliation><affiliation>Department of Neurology, Laboratory Medicine and Pathology,</affiliation><affiliation>Department of Laboratory Medicine and Pathology and</affiliation><affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gwennaelle</namePart><namePart type="family">Auregan</namePart><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Noelle</namePart><namePart type="family">Dufour</namePart><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Martine</namePart><namePart type="family">Guillermier</namePart><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Emmanuel</namePart><namePart type="family">Brouillet</namePart><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Philippe</namePart><namePart type="family">Hantraye</namePart><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nicole</namePart><namePart type="family">Dglon</namePart><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Robert J.</namePart><namePart type="family">Ferrante</namePart><affiliation>Geriatric Research Education and Clinical Center, Bedford Veterans Administration Medical Center, Bedford, MA 01730, USA,</affiliation><affiliation>Department of Neurology, Laboratory Medicine and Pathology,</affiliation><affiliation>Department of Laboratory Medicine and Pathology and</affiliation><affiliation>Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gilles</namePart><namePart type="family">Bonvento</namePart><affiliation>CEA, Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>CNRS CEA URA 2210, F-92265 Fontenay-aux-Roses, France,</affiliation><affiliation>E-mail: gilles.bonvento@cea.fr</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2010-08-01</dateIssued><dateCreated encoding="w3cdtf">2010-05-21</dateCreated><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><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.</abstract><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>19</number></detail><detail type="issue"><caption>no.</caption><number>15</number></detail><extent unit="pages"><start>3053</start><end>3067</end></extent></part></relatedItem><identifier type="istex">C34BFFA73C9DE9284564A3AC573DBE243FEF96B8</identifier><identifier type="DOI">10.1093/hmg/ddq212</identifier><identifier type="ArticleID">ddq212</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2010. 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