Involvement of HDAC1 and HDAC3 in the Pathology of Polyglutamine Disorders: Therapeutic Implications for Selective HDAC1/HDAC3 Inhibitors.
Involvement of HDAC1 and HDAC3 in the Pathology of Polyglutamine Disorders: Therapeutic Implications for Selective HDAC1/HDAC3 Inhibitors.
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DOI：
10.3390/ph7060634
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发表时间：
2014-05-26
期刊：
影响因子：
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通讯作者：
Thomas EA
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文献类型：
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作者：
Thomas EA
组蛋白脱乙酰酶 (HDAC) 影响组蛋白和其他重要细胞蛋白的乙酰化状态，已被认为是广泛人类疾病的潜在有用治疗靶点。新兴研究表明，不同类型的 HDAC 抑制剂在神经系统疾病的各种实验模型中显示出有益的作用。 HDAC 酶由一个大的蛋白质家族组成，目前在人类中发现了 18 种 HDAC 酶。因此，HDAC 抑制剂治疗的一个重要问题是哪种 HDAC 酶对于改善疾病表型很重要，因为已经清楚各个 HDAC 酶在大脑中发挥不同的生物学作用。本综述将讨论支持 HDAC1 和 HDAC3 参与多聚谷氨酰胺疾病（包括亨廷顿病）的证据，以及使用 HDAC1 和 HDAC3 选择性 HDAC 抑制剂作为这些疾病的治疗干预。此外，虽然已知 HDAC 抑制剂会改变染色质结构，导致基因转录发生变化，但了解这些化合物临床前功效的确切机制仍然是一个挑战。还将讨论选择性 HDAC 抑制剂的潜在染色质相关和非染色质相关作用机制。
Histone deacetylases (HDACs) enzymes, which affect the acetylation status of histones and other important cellular proteins, have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Emerging studies have demonstrated that different types of HDAC inhibitors show beneficial effects in various experimental models of neurological disorders. HDAC enzymes comprise a large family of proteins, with18 HDAC enzymes currently identified in humans. Hence, an important question for HDAC inhibitor therapeutics is which HDAC enzyme(s) is/are important for the amelioration of disease phenotypes, as it has become clear that individual HDAC enzymes play different biological roles in the brain. This review will discuss evidence supporting the involvement of HDAC1 and HDAC3 in polyglutamine disorders, including Huntington’s disease, and the use of HDAC1- and HDAC3-selective HDAC inhibitors as therapeutic intervention for these disorders. Further, while HDAC inhibitors are known alter chromatin structure resulting in changes in gene transcription, understanding the exact mechanisms responsible for the preclinical efficacy of these compounds remains a challenge. The potential chromatin-related and non-chromatin-related mechanisms of action of selective HDAC inhibitors will also be discussed.