Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders

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Epigenetic chromatin remodeling and modifications of DNA represent central mechanisms for regulation of gene expression during brain development and in memory formation. Emerging evidence implicates epigenetic modifications in disorders of synaptic plasticity and cognition. This review focuses on recent findings that HDAC inhibitors can ameliorate deficits in synaptic plasticity, cognition, and stress-related behaviors in a wide range of neurologic and psychiatric disorders including Huntington's disease, Parkinson's disease, anxiety and mood disorders, Rubinstein-Taybi syndrome, and Rett syndrome. These agents may prove useful in the clinic for the treatment of the cognitive impairments that are central elements of many neurodevelopmental, neurological, and psychiatric disorders.

Introduction

Recent findings implicate epigenetic modifications in the etiology of neurodegenerative and psychiatric disorders. Covalent epigenetic modifications of conserved lysine residues in the amino-terminal tails of histone proteins and methylation of DNA at CpG dinucleotides control accessibility of chromatin to the core transcriptional machinery and play an essential role in determining the activation state of genes. An array of post-translational histone modifications are known and these include acetylation, methylation, ubiquitination, phosphorylation, and SUMOlyation, all of which can serve as epigenetic tags (for review, see [1, 2, 3]). These modifications alter chromatin structure and make specific regions of the genome more or less accessible to the transcriptional machinery. Epigenetic remodeling is crucial to cellular differentiation, development, and behavior, including learning and memory [1, 4, 5]. The epigenome is responsive to synaptic activity and provides a link between experience, genetic predisposition, and changes in neural function. Chromatin modifications are not static but dynamically change in a cell-specific manner during development and in response to external stimuli including neuronal insults. Epigenetic dysregulation is a common theme in disorders of synaptic plasticity and cognition including neurodegenerative disorders (Huntington's disease, Parkinson's disease (PD), and ischemia), mood disorders (depression and anxiety), and neurodevelopmental disorders (Rubinstein-Taybi syndrome (RTS), Rett syndrome (RS), and Fragile X syndrome). This article reviews new insight into the molecular mechanisms underlying activity-dependent remodeling of the epigenome under physiological and pathological conditions and highlights the importance of epigenetic modifications in developing new therapeutic approaches for psychiatric and neurological disorders.

Section snippets

Histone modifications and transcriptional regulation

Histone modifications regulate gene expression in three mechanistic ways [1, 2, 3]. First, they regulate chromatin structure, making genetic loci more or less accessible to the transcriptional machinery. Second, they serve a signaling role by integrating responses to multiple biochemical signaling cascades and recruit or repel the transcriptional machinery and chromatin remodeling complexes. Third, and perhaps most interestingly, histone modifications mediate epigenetic changes in gene

Histone acetyltransferases

Histone acetylation has received much attention in the nervous system in part because of our knowledge of the enzymatic machinery and signal transduction mechanisms that regulate this post-translational modification. Acetylation of core histones is catalyzed by transcriptional coactivators such as CREB-binding protein (CBP), which possess histone acetyltransferase (HAT) activity [1, 6]. Histone acetylation remodels chromatin structure, thereby modulating transcription [1, 6]. Specificity of

Histone deacetylases

Histone deacetylases (HDACs) remove acetyl groups from lysine/arginine residues in the amino-terminal tails of core histones and other proteins, thus reversing the effects of the HATs [1, 6]. Deacetylation of histone proteins shifts the balance toward chromatin condensation and thereby silences gene expression. Unlike HATs, HDACs have a rich structural diversity, which confers diversity of function and renders HDACs promising targets for drug discovery and therapeutic intervention. Many HDACs

HDAC inhibitors

Recent years have witnessed an explosion in the development of new HDAC inhibitors [7]. HDAC inhibitors can be classified into four main chemical families, the short-chain fatty acids (e.g. sodium butyrate, phenylbutyrate, and valproic acid), the hyroxamic acids (e.g. trichostatin A and suberoylanilide hydroxamic acid (SAHA)), the epoxyketones (e.g. trapoxin), and the benzamides. Of these, the most widely studied are sodium butyrate, phenylbutyrate, trichostatin A, and SAHA. The butyrates are

Huntington's disease

A role for HDACs in neurodegenerative disorders was first hinted at by experiments that showed that HDAC inhibitors ameliorate the cognitive and motor deficits characteristic of Huntington's disease (HD). HD is an inherited, late onset autosomal-dominant neurodegenerative disorder characterized by progressive motor, psychiatric, and cognitive decline that affects 1 person per 10 000 people of Western European descent [9]. Marked neuronal loss occurs in the cortex and striatum. HD is caused by a

Depression

One psychiatric disorder for which strong evidence exists to suggest that histone acetylation represents a valid therapeutic target is depression [30]. Major depressive disorder is a very common disorder, with a lifetime risk of 16.2% in the United States [31]. Thus, the development of novel antidepressants with greater efficacy would serve a large potential patient market. One drawback of current antidepressant medications, most of which act to increase synaptic levels of serotonin or

Rubinstein-Taybi syndrome

Early evidence for a role for epigenetic pathways in brain came from studies showing that the developmental disorders associated with RTS result from heterozygous mutations in the transcriptional coactivator CBP or its homolog p300 [40, 41]. RTS is a well-defined inherited, autosomal-dominant disease that occurs once in 125 000 births, and accounts for 1 in 300 patients with mental retardation [42]. Physical traits associated with RTS include altered facial abnormalities, broad digits/fingers

Future directions and conclusions

Here, we have described a variety of neurodegenerative, psychiatric, and neurobehavioral disorders that involve alterations in histone modifications and can be reversed, at least in part, by treatment with HDAC inhibitors. Will HDAC inhibitors treat all ills or will specific classes of HDAC inhibitors be identified to target specific disorders? A common theme that emerges among the diverse neuropsychiatric disorders reviewed in this article is that many of these disorders share a commonality of

Conflict of interest

None.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • •• of outstanding interest

Acknowledgements

This work was supported by NIH grant NS46742 to RSZ, NIH grant MH60244 to TA, and a generous grant from the F.M. Kirby Program in Neural Repair and Neuroprotection to RSZ.

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