title: Mutant huntingtin represses CBP, but not p300, by binding and protein degradation.
abstract: Huntington's disease can be used as a model to study neurodegenerative disorders caused by aggregation-prone proteins. It has been proposed that the entrapment of transcription factors in aggregates plays an important role in pathogenesis. We now report that the transcriptional activity of CBP is already repressed in the early time points by soluble mutant huntingtin, whereas the histone acetylase activity of CBP/p300 is gradually diminished over time. Mutant huntingtin bound much stronger to CBP than normal huntingtin, possibly contributing to repression. Especially at the later time points, CBP protein level was gradually reduced via the proteasome pathway. In sharp contrast, p300 was unaffected by mutant huntingtin. This selective degradation of CBP was absent in spinocerebellar ataxia 3. Thus, mutant huntingtin specifically affects CBP and not p300 both at the early and later time points, via multiple mechanisms. In addition to the reduction of CBP, also the altered ratio of these closely related histone acetyl transferases may affect chromatin structure and transcription and thus contribute to neurodegeneration.
authors.affiliation: CBG-Center of Human and Clinical Genetics, Leiden University Medical Center, The Netherlands, and Department of Neurology, The second affiliated hospital of China Medical University, Shenyang, China.
authors.forename: Shu-Yan
authors.initials: SY
authors.lastname: Cong
authors.forename: Barry A
authors.initials: BA
authors.lastname: Pepers
authors.forename: Bernd O
authors.initials: BO
authors.lastname: Evert
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
authors.forename: Raymund A C
authors.initials: RA
authors.lastname: Roos
authors.forename: Gert-Jan B
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: Josephine C
authors.initials: JC
authors.lastname: Dorsman
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D050882:CREB-Binding Protein / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology*; D051548:Histone Acetyltransferases / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017827:Machado-Joseph Disease / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D050436:Regulatory Elements, Transcriptional / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D051548:Histone Acetyltransferases; D050880:p300-CBP Transcription Factors; D046988:Proteasome Endopeptidase Complex