Histone deacetylases: Focus on the nervous system

Abstract

Neurodegenerative disease strikes millions worldwide and there is mounting evidence suggesting that underlying the onset and progression of these debilitating diseases is inappropriate neuronal apoptosis. Recent reports have implicated a family of proteins known as histone deacetylases (HDACs) in various neuronal processes including the neuronal death program. Initial headway in this field has been made largely through the use of broad-spectrum HDAC inhibitors. In fact, pharmacological inhibition of HDAC activity has been shown to protect neurons in several models of neurodegeneration. The observation that HDAC inhibitors can have opposing effects in different paradigms of neurodegeneration suggests that individual members of the HDAC protein family may play distinct roles that could depend on the specific cell type under study. The purpose of this review is to detail work involving the use of HDAC inhibitors within the context of neurodegeneration and examine the roles of individual HDAC members in the nervous system with specific focus on neuronal cell death.

Histone deacetylases 1 and 2 are expressed at distinct stages of neuro‐glial development

“…In support of this, HDAC inhibitors, such as VPA and TSA, can alter neurite outgrowth (Hao et al, 2004;Laeng et al, 2004) and prevent the expression of critical photoreceptor genes in retinal development, respectively (Chen and Cepko, 2007). In addition, VPA and TSA can reduce ischemic infarcts (Endres et al, 2000;Ren et al, 2004) and HDAC inhibitors can ameliorate the symptoms of multiple neurodegenerative disorders, including Huntington's Disease and ALS (reviewed in Morrison et al, 2007). In this context, HDAC inhibitors have been proposed to re-establish the balance between histone deacetylation and acetylation activity, the loss of which can underlie neuronal dysfunction and degeneration (Saha and Pahan, 2006).…”

“…HDAC inhibitors, such as valproic acid (Gottlicher et al, 2001;Phiel et al, 2001), are often employed, both clinically and in experimental manipulations of nervous system function (Tunnicliff, 1999;Saha and Pahan, 2006;Morrison et al, 2007). The development and function of the nervous system appears to be particularly sensitive to disruptions in epigenetic gene regulation, leading to syndromes associated with mental retardation (reviewed in Egger et al, 2004), as well as complex psychiatric disorders such as schizophrenia (Veldic et al, 2004;Grayson et al, 2005).…”

Molecular and pathologic insights from latent HIV-1 infection in the human brain

“…32 Valproic acid and trichostatin A were unable to reactivate HIV in latently infected primary CD4 T cells, 33 raising concerns about their potential use in neuroAIDS. Modulation of BCL11B could represent an alternative therapeutic strategy for eradication of reservoirs.…”

Epigenetic Mechanisms in Stroke and Epilepsy

“…The HDAC superfamily is made up of four classes (class I, II, III, IV), with class I and II being the most studied with prominent expression in the brain (for review see: (Gray and Ekstrom, 2001;de Ruijter et al, 2003;Morrison et al, 2007;Haggarty and Tsai, 2011)). HDACs remove acetyl groups from core histone proteins, thereby condensing the chromatin and repressing transcription.…”

“…HDACs remove acetyl groups from core histone proteins, thereby condensing the chromatin and repressing transcription. HDACs also remove acetyl moieties from other proteins such as transcription factors and thereby alter cellular function (Morrison et al, 2007;Morris et al, 2010). HDACs do not bind DNA directly, but rather function as part of a multi-protein complex to recognize other factors such as transcriptional activators and repressors, which direct them to their target genes (de Ruijter et al, 2003;Carey and La Thangue, 2006).…”