Sadri-Vakili Ghazaleh, Cha Jang-Ho J
Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street/B114-2001, Charlestown, MA 02129-4404, USA.
Curr Alzheimer Res. 2006 Sep;3(4):403-8. doi: 10.2174/156720506778249407.
Huntington's disease is an autosomal dominantly inherited neurodegenerative disorder caused by a polyglutamine repeat expansion. The onset of HD leads to problems with movement, cognition, and behavioral functioning and there is currently no effective treatment. The mechanism by which mutant huntingtin causes neuronal dysfunction is not known. However, multiple pathologic mechanisms have been discovered. Recent studies provide strong evidence for transcriptional dysregulation as a mechanism of HD pathogenesis. The control of eukaryotic gene expression depends on the modification of histone proteins associated with specific genes; acetylation and deacetylation of histones play a critical role in gene expression. Studies in numerous HD models have shown that mutant huntingtin expression leads to a change in histone acetyl transferase (HAT) activity and suggest that aberrant HAT activity may be an underlying mechanism of transcriptional dysregulation in HD. Furthermore, recent studies have shown a therapeutic role for histone deacetylase (HDAC) inhibitors in a number of HD models. In this review we discuss a number of studies that use HDAC inhibitors as therapeutic agents in HD models. These studies demonstrate that HDAC inhibitors are a promising therapeutic approach for the treatment of HD.
亨廷顿舞蹈症是一种由多聚谷氨酰胺重复序列扩增引起的常染色体显性遗传神经退行性疾病。亨廷顿舞蹈症的发病会导致运动、认知和行为功能方面的问题，目前尚无有效治疗方法。突变的亨廷顿蛋白导致神经元功能障碍的机制尚不清楚。然而，已经发现了多种病理机制。最近的研究为转录失调作为亨廷顿舞蹈症发病机制提供了有力证据。真核基因表达的调控依赖于与特定基因相关的组蛋白修饰；组蛋白的乙酰化和去乙酰化在基因表达中起关键作用。在众多亨廷顿舞蹈症模型中的研究表明，突变的亨廷顿蛋白表达会导致组蛋白乙酰转移酶（HAT）活性改变，并提示异常的HAT活性可能是亨廷顿舞蹈症转录失调的潜在机制。此外，最近的研究表明组蛋白去乙酰化酶（HDAC）抑制剂在一些亨廷顿舞蹈症模型中具有治疗作用。在本综述中，我们讨论了一些在亨廷顿舞蹈症模型中使用HDAC抑制剂作为治疗药物的研究。这些研究表明，HDAC抑制剂是治疗亨廷顿舞蹈症的一种有前景的治疗方法。
