Morris Michael J, Monteggia Lisa M
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
Int J Dev Neurosci. 2013 Oct;31(6):370-81. doi: 10.1016/j.ijdevneu.2013.02.005. Epub 2013 Mar 4.
Non-specific pharmacological inhibition of the histone deacetylase (HDAC) family of enzymes has largely beneficial effects in a variety of diverse contexts including cancer, cognitive function, and neurodegeneration. This review will discuss the role of individual HDAC isoforms in brain function during development and in the adult. Importantly class I and class II HDACs exhibit distinct cellular and subcellular expression patterns and utilize different signaling pathways to influence their substrates. Moreover, dissociable phenotypic outcomes emerge following manipulation of individual HDACs in the brain. To date, pharmacological inhibitors capable of targeting individual HDACs have proven difficult to develop, an obstacle that must be overcome to unlock the substantial clinical promise of manipulating endogenous HDAC isoforms in the central nervous system.
对组蛋白去乙酰化酶(HDAC)家族酶的非特异性药理抑制在包括癌症、认知功能和神经退行性变等多种不同情况下具有很大的有益作用。本综述将讨论个体HDAC亚型在发育过程中和成体大脑功能中的作用。重要的是,I类和II类HDAC表现出不同的细胞和亚细胞表达模式,并利用不同的信号通路来影响其底物。此外,在大脑中对个体HDAC进行操作后会出现可分离的表型结果。迄今为止,已证明难以开发能够靶向个体HDAC的药理抑制剂,这是一个必须克服的障碍,以便释放操纵中枢神经系统内源性HDAC亚型的巨大临床前景。