Depletion of CBP is directly linked with cellular toxicity caused by mutant huntingtin.
Huntington's disease is a neurodegenerative disease caused by an expanded polyglutamine stretch within the huntingtin protein. Transfection of mutant huntingtin causes cell toxicity and depletion of CREB binding protein (CBP) or its recruitment into huntingtin aggregates. However, the role of CBP has been controversial and the relationship between polyglutamine-induced toxicity and CBP depletion has not been examined on an individual cell basis. Using a single-cell based assay, we found that, in HT22 cells or primary neurons transfected with mutant huntingtin, cell toxicity was accompanied by CBP depletion, rather than merely recruitment. Transfection with a htt exon1 construct containing uninterrupted polyglutamine or a polyglutamine region engineered to form a compact beta structure resulted in cell toxicity. CBP depletion was accompanied by histone hypo-acetylation. CBP overexpression rescued both acetylated histone levels and cell toxicity. These data suggest that CBP dysfunction and altered gene transcription contribute to mutant htt-induced neurotoxicity.
Jiang
Haibing
H
Division of Neurobiology, Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Poirier
Michelle A
MA
Liang
Yideng
Y
Pei
Zhong
Z
Weiskittel
Charlotte E
CE
Smith
Wanli W
WW
DeFranco
Donald B
DB
Ross
Christopher A
CA
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D050882:CREB-Binding Protein / Q000172:deficiency*; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D051548:Histone Acetyltransferases / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D051548:Histone Acetyltransferases