Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1 Export

@article{citeulike:3054080, 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. 10.1093/hmg/ddm162}, author = {Goold, Robert and Hubank, Michael and Hunt, Abigail and Holton, Janice and Menon, Rajesh P. and Revesz, Tamas and Pandolfo, Massimo and Matilla-Duenas, Antoni}, citeulike-article-id = {3054080}, citeulike-linkout-0 = {http://dx.doi.org/10.1093/hmg/ddm162}, citeulike-linkout-1 = {http://hmg.oxfordjournals.org/cgi/content/abstract/16/17/2122}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/17599952}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=17599952}, day = {1}, doi = {10.1093/hmg/ddm162}, journal = {Hum. Mol. Genet.}, keywords = {ataxin, dopamine, neurodegredation, thyroid}, month = {September}, number = {17}, pages = {2122--2134}, posted-at = {2008-07-28 20:45:08}, priority = {2}, title = {Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1}, url = {http://dx.doi.org/10.1093/hmg/ddm162}, volume = {16}, year = {2007} }

TY - JOUR ID - citeulike:3054080 L3 - citeulike-article-id:3054080 N2 - 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. 10.1093/hmg/ddm162 IS - 17 JF - Hum. Mol. Genet. EP - 2134 TI - Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1 VL - 16 SP - 2122 KW - ataxin KW - dopamine KW - neurodegredation KW - thyroid AU - Goold, Robert AU - Hubank, Michael AU - Hunt, Abigail AU - Holton, Janice AU - Menon, Rajesh AU - Revesz, Tamas AU - Pandolfo, Massimo AU - Matilla-Duenas, Antoni PY - 2007/09/01/ UR - http://dx.doi.org/10.1093/hmg/ddm162 ER -