title: Interaction of Huntington disease protein with transcriptional activator Sp1.
abstract: Polyglutamine expansion causes Huntington disease (HD) and at least seven other neurodegenerative diseases. In HD, N-terminal fragments of huntingtin with an expanded glutamine tract are able to aggregate and accumulate in the nucleus. Although intranuclear huntingtin affects the expression of numerous genes, the mechanism of this nuclear effect is unknown. Here we report that huntingtin interacts with Sp1, a transcription factor that binds to GC-rich elements in certain promoters and activates transcription of the corresponding genes. In vitro binding and immunoprecipitation assays show that polyglutamine expansion enhances the interaction of N-terminal huntingtin with Sp1. In HD transgenic mice (R6/2) that express N-terminal-mutant huntingtin, Sp1 binds to the soluble form of mutant huntingtin but not to aggregated huntingtin. Mutant huntingtin inhibits the binding of nuclear Sp1 to the promoter of nerve growth factor receptor and suppresses its transcriptional activity in cultured cells. Overexpression of Sp1 reduces the cellular toxicity and neuritic extension defects caused by intranuclear mutant huntingtin. These findings suggest that the soluble form of mutant huntingtin in the nucleus may cause cellular dysfunction by binding to Sp1 and thus reducing the expression of Sp1-regulated genes.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Li
authors.forename: Anna L
authors.initials: AL
authors.lastname: Cheng
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lam
authors.forename: Manjula
authors.initials: M
authors.lastname: Rao
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
mesh_terms: D000818:Animals; D002451:Cell Compartmentation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic; D019680:Trinucleotide Repeat Expansion
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D017475:Receptors, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; D016329:Sp1 Transcription Factor; C097188:polyglutamine