title: Suppression of aggregate formation of mutant huntingtin potentiates CREB-binding protein sequestration and apoptotic cell death.
abstract: Although aggregates of mutant huntingtin are a pathological hallmark of Huntington's disease (HD), the role of inclusions in the pathogenesis remains inconclusive. Sequestration of CBP into mutant huntingtin has been reported to play a significant role in the pathogenesis of HD. However, whether aggregate formation of mutant huntingtin is necessary for the sequestration of CBP is not fully elucidated. In the present study, YFP was linked into either N- or C-terminus of exon 1 huntingtin to modulate the aggregation propensity of huntingtin. Efficient aggregation was observed with C-terminally YFP-tagged huntingtin (MT-YFP) whereas N-terminally YFP-tagged mutant huntingtin (YFP-MT) exhibited significantly attenuated aggregation frequency. The sequestration of CBP and apoptosis were significantly increased with YFP-MT. Microarray study showed transcriptional changes favoring apoptosis. Furthermore, expression of PGC1-α was significantly decreased with YFP-MT. The data strongly demonstrate that microscopically non-aggregate form of mutant huntingtin might exert essential pathogenic role of mutant huntingtin in HD.
authors: Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon, South Korea.
authors: Yong-Joon
authors: YJ
authors: Choi
authors: Song-In
authors: SI
authors: Kim
authors: Jae-Won
authors: JW
authors: Lee
authors: Yong-Soo
authors: YS
authors: Kwon
authors: Hee Jae
authors: HJ
authors: Lee
authors: Sung-Soo
authors: SS
authors: Kim
authors: Wanjoo
authors: W
authors: Chun
mesh_terms: D017209:Apoptosis / Q000235:genetics; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005091:Exons / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: C086055:HTT protein, human; D006360:Heat-Shock Proteins; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D050882:CREB-Binding Protein; C494363:CREBBP protein, human