Department of Medical and Molecular Genetics, King's College London London, UK.
Department of Social Medicine, Poznan University of Medical Sciences Poznan, Poland.
Front Cell Neurosci. 2015 Feb 24;9:42. doi: 10.3389/fncel.2015.00042. eCollection 2015.
For the past decade protein acetylation has been shown to be a crucial post-transcriptional modification involved in the regulation of protein functions. Histone acetyltransferases (HATs) mediate acetylation of histones which results in the nucleosomal relaxation associated with gene expression. The reverse reaction, histone deacetylation, is mediated by histone deacetylases (HDACs) leading to chromatin condensation followed by transcriptional repression. HDACs are divided into distinct classes: I, IIa, IIb, III, and IV, on the basis of size and sequence homology, as well as formation of distinct repressor complexes. Implications of HDACs in many diseases, such as cancer, heart failure, and neurodegeneration, have identified these molecules as unique and attractive therapeutic targets. The emergence of HDAC4 among the members of class IIa family as a major player in synaptic plasticity raises important questions about its functions in the brain. The characterization of HDAC4 specific substrates and molecular partners in the brain will not only provide a better understanding of HDAC4 biological functions but also might help to develop new therapeutic strategies to target numerous malignancies. In this review we highlight and summarize recent achievements in understanding the biological role of HDAC4 in neurodegenerative processes.
在过去的十年中，蛋白质乙酰化已被证明是一种至关重要的转录后修饰，参与蛋白质功能的调节。组蛋白乙酰转移酶（HATs）介导组蛋白的乙酰化，导致核小体松弛，与基因表达相关。相反的反应，组蛋白去乙酰化，由组蛋白去乙酰化酶（HDACs）介导，导致染色质凝聚，随后转录抑制。HDACs 根据大小和序列同源性以及形成不同的抑制复合物，分为 I、IIa、IIb、III 和 IV 类。HDACs 在许多疾病中的作用，如癌症、心力衰竭和神经退行性变，已将这些分子确定为独特且有吸引力的治疗靶点。IIa 家族成员中的 HDAC4 作为突触可塑性的主要参与者的出现，提出了关于其在大脑中的功能的重要问题。在大脑中鉴定 HDAC4 特异性底物和分子伴侣不仅将提供对 HDAC4 生物学功能的更好理解，而且可能有助于开发针对众多恶性肿瘤的新的治疗策略。在这篇综述中，我们强调并总结了理解 HDAC4 在神经退行性过程中的生物学作用的最新成就。
