Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1
Identifieur interne : 001477 ( Main/Exploration ); précédent : 001476; suivant : 001478Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1
Auteurs : Robert Goold ; Michael Hubank ; Abigail Hunt ; Janice Holton ; Rajesh P. Menon [Royaume-Uni] ; Tamas Revesz ; Massimo Pandolfo [Belgique] ; Antoni Matilla-DueasSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2007-09-01.
Abstract
Ataxin 1 (Atxn1) is a protein of unknown function associated with spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease of late onset with variable degrees of cerebellar ataxia, ophthalmoplegia and neuropathy. SCA1 is caused by the toxic effects triggered by an expanded polyglutamine (polyQ) within Atxn1 resulting in neurodegeneration in the cerebellum, brain stem and spinocerebellar tracts. To gain insights into Atxn1 function, we have analysed the cerebellar gene expression profiles by microarray analysis in Atxn1-null mice, and identified alterations in expression of genes regulated by Sp1-dependent transcription, including the dopamine receptor D2 (Drd2), retinoic acid/thyroid hormone and Wnt-signalling. Interestingly, Drd2 expression levels are reduced in both Atxn1-null and transgenic mice expressing a pathogenic human Atxn1 with an expanded polyglutamine in cerebellar Purkinje cells. Our co-transfection experiments in human neuroblastoma SH-SY5Y cells and luciferase assays provide evidence for transcriptional regulation of Drd2 by Atxn1 and its AXH module. We show that Atxn1 occupies at the Drd2 promoter in vivo, and interacts and functions synergistically with the zinc-finger transcription factor Sp1 to co-regulate Drd2 expression. The interaction and transcriptional effects are mediated by the AXH domain within Atxn1 and are abrogated by the expanded polyQ within Atxn1. Therefore, this study identifies novel molecular targets that are regulated by Atxn1 which might contribute to the motor deficits in SCA1, and provides new insights into the mechanisms by which Atxn1 co-regulates transcription.
Url:
DOI: 10.1093/hmg/ddm162
Affiliations:
- Belgique, Royaume-Uni
- Angleterre, Grand Londres, Région de Bruxelles-Capitale
- Bruxelles, Londres
- Université libre de Bruxelles
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SCA1 is caused by the toxic effects triggered by an expanded polyglutamine (polyQ) within Atxn1 resulting in neurodegeneration in the cerebellum, brain stem and spinocerebellar tracts. To gain insights into Atxn1 function, we have analysed the cerebellar gene expression profiles by microarray analysis in Atxn1-null mice, and identified alterations in expression of genes regulated by Sp1-dependent transcription, including the dopamine receptor D2 (Drd2), retinoic acid/thyroid hormone and Wnt-signalling. Interestingly, Drd2 expression levels are reduced in both Atxn1-null and transgenic mice expressing a pathogenic human Atxn1 with an expanded polyglutamine in cerebellar Purkinje cells. Our co-transfection experiments in human neuroblastoma SH-SY5Y cells and luciferase assays provide evidence for transcriptional regulation of Drd2 by Atxn1 and its AXH module. We show that Atxn1 occupies at the Drd2 promoter in vivo, and interacts and functions synergistically with the zinc-finger transcription factor Sp1 to co-regulate Drd2 expression. The interaction and transcriptional effects are mediated by the AXH domain within Atxn1 and are abrogated by the expanded polyQ within Atxn1. Therefore, this study identifies novel molecular targets that are regulated by Atxn1 which might contribute to the motor deficits in SCA1, and provides new insights into the mechanisms by which Atxn1 co-regulates transcription.</div></front></TEI><affiliations><list><country><li>Belgique</li><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Grand Londres</li><li>Région de Bruxelles-Capitale</li></region><settlement><li>Bruxelles</li><li>Londres</li></settlement><orgName><li>Université libre de Bruxelles</li></orgName></list><tree><noCountry><name sortKey="Goold, Robert" sort="Goold, Robert" uniqKey="Goold R" first="Robert" last="Goold">Robert Goold</name><name sortKey="Holton, Janice" sort="Holton, Janice" uniqKey="Holton J" first="Janice" last="Holton">Janice Holton</name><name sortKey="Hubank, Michael" sort="Hubank, Michael" uniqKey="Hubank M" first="Michael" last="Hubank">Michael Hubank</name><name sortKey="Hunt, Abigail" sort="Hunt, Abigail" uniqKey="Hunt A" first="Abigail" last="Hunt">Abigail Hunt</name><name sortKey="Matilla Dueas, Antoni" sort="Matilla Dueas, Antoni" uniqKey="Matilla Dueas A" first="Antoni" last="Matilla-Dueas">Antoni Matilla-Dueas</name><name sortKey="Revesz, Tamas" sort="Revesz, Tamas" uniqKey="Revesz T" first="Tamas" last="Revesz">Tamas Revesz</name></noCountry><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Menon, Rajesh P" sort="Menon, Rajesh P" uniqKey="Menon R" first="Rajesh P." last="Menon">Rajesh P. Menon</name></region></country><country name="Belgique"><region name="Région de Bruxelles-Capitale"><name sortKey="Pandolfo, Massimo" sort="Pandolfo, Massimo" uniqKey="Pandolfo M" first="Massimo" last="Pandolfo">Massimo Pandolfo</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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