Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease.
Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis. Here, we report that huntingtin interacts with the transcriptional activator Sp1 and coactivator TAFII130. Coexpression of Sp1 and TAFII130 in cultured striatal cells from wild-type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity. Furthermore, soluble mutant huntingtin inhibits Sp1 binding to DNA in postmortem brain tissues of both presymptomatic and affected HD patients. Understanding these early molecular events in HD may provide an opportunity to interfere with the effects of mutant huntingtin before the development of disease symptoms.
Dunah
Anthone W
AW
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Center for Aging, Genetics and Neurodegeneration, Charlestown, MA 02129, USA.
Jeong
Hyunkyung
H
Griffin
April
A
Kim
Yong-Man
YM
Standaert
David G
DG
Hersch
Steven M
SM
Mouradian
M Maral
MM
Young
Anne B
AB
Tanese
Naoko
N
Krainc
Dimitri
D
D000818:Animals; D001921:Brain / Q000378:metabolism; D002421:Caudate Nucleus / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010455:Peptides; D011401:Promoter Regions, Genetic; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000235:genetics; D012995:Solubility; D016329:Sp1 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D019680:Trinucleotide Repeat Expansion; D020798:Two-Hybrid System Techniques
D004268:DNA-Binding Proteins; C086055:HTT protein, human; C506812:Htt protein, mouse; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D017448:Receptors, Dopamine D2; D016329:Sp1 Transcription Factor; C101882:TAF4 protein, human; C523528:TAF4 protein, mouse; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors; C097188:polyglutamine; D004247:DNA