Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington's Disease Mice
Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington's Disease Mice
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DOI：
10.1523/jneurosci.23-28-09418.2003
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发表时间：
2003-10
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通讯作者：
R. Ferrante;James K. Kubilus;Junghee Lee;H. Ryu;A. Beesen;B. Zucker;Karen M. Smith;N. Kowall;R. Ratan;R. Luthi-Carter;S. Hersch
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作者：
R. Ferrante;James K. Kubilus;Junghee Lee;H. Ryu;A. Beesen;B. Zucker;Karen M. Smith;N. Kowall;R. Ratan;R. Luthi-Carter;S. Hersch
亨廷顿舞蹈病（HD）神经元死亡的确切原因尚不清楚。虽然没有发现突变亨廷顿蛋白的单一特异性蛋白-蛋白相互作用是病理触发因素，但转录功能障碍可能导致HD中观察到的神经退行性变。在R6/2转基因HD小鼠模型中，使用组蛋白去乙酰化酶抑制剂丁酸钠调节转录的药物治疗以剂量依赖的方式显著延长了生存期，改善了体重和运动表现，并延缓了神经病理后遗症。丁酸钠也增加组蛋白和特异性蛋白-1乙酰化，并保护3-硝基丙酸神经毒性。微阵列分析显示，丁酸钠处理的R6/2小鼠α-和β-珠蛋白以及MAP激酶磷酸酶-1的表达增加，表明氧化磷酸化和转录调控得到改善。这些发现加强了转录功能障碍在HD发病机制中起作用的假设，并表明旨在调节转录的治疗可能针对HD早期病理事件，并为HD患者提供临床益处。
The precise cause of neuronal death in Huntington's disease (HD) is unknown. Although no single specific protein-protein interaction of mutant huntingtin has emerged as the pathologic trigger, transcriptional dysfunction may contribute to the neurodegeneration observed in HD. Pharmacological treatment using the histone deacetylase inhibitor sodium butyrate to modulate transcription significantly extended survival in a dose-dependent manner, improved body weight and motor performance, and delayed the neuropathological sequelae in the R6/2 transgenic mouse model of HD. Sodium butyrate also increased histone and Specificity protein-1 acetylation and protected against 3-nitropropionic acid neurotoxicity. Microarray analysis showed increased expression of α- and β-globins and MAP kinase phosphatase-1 in sodium butyrate-treated R6/2 mice, indicative of improved oxidative phosphorylation and transcriptional regulation. These findings strengthen the hypothesis that transcriptional dysfunction plays a role in the pathogenesis of HD and suggest that therapies aimed at modulating transcription may target early pathological events and provide clinical benefits to HD patients.