Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein.
Sequestration of the transcriptional coactivator CREB-binding protein (CBP), a histone acetyltransferase, has been implicated in the pathogenesis of polyglutamine expansion neurodegenerative disease. We used a Drosophila model to demonstrate that polyglutamine-induced neurodegeneration is accompanied by a defect in histone acetylation and a substantial alteration in the transcription profile. Furthermore, we demonstrate complete functional and morphological rescue by up-regulation of endogenous Drosophila CBP (dCBP). Rescue of the degenerative phenotype is associated with eradication of polyglutamine aggregates, recovery of histone acetylation, and normalization of the transcription profile. These findings suggest that histone acetylation is an early target of polyglutamine toxicity and indicate that transcriptional dysregulation is an important part of the pathogenesis of polyglutamine-induced neurodegeneration.
Taylor
J Paul
JP
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1250, USA.
Taye
Addis A
AA
Campbell
Catherine
C
Kazemi-Esfarjani
Parsa
P
Fischbeck
Kenneth H
KH
Min
Kyung-Tai
KT
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D050882:CREB-Binding Protein; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases; D009154:Mutation; D009474:Neurons / Q000473:pathology / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics* / Q000503:physiopathology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D009687:Nuclear Proteins; D010455:Peptides; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; C097188:polyglutamine; D000123:Acetyltransferases; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases