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Histone deacetylase inhibitors as therapeutics for polyglutamine disorders

Key Points

  • Transcriptional dysregulation is part of the pathogenic mechanism that underlies neuronal dysfunction in polyglutamine repeat diseases such as Huntington's disease (HD). Microarray experiments show that the expression of a subset of genes is robustly altered in mouse models of HD and in the brains of patients with HD.

  • Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are enzymes that control transcription by acetylating and deacetylating histones, thereby changing the conformation of chromatin structure.

  • Expanded polyglutamine repeat proteins adopt aberrant interactions with HATs and HDACs as well as other transcription factors, co-activators and co-repressors owing to conformational changes caused by the polyglutamine stretch within the mutant protein.

  • Of the four classes of HDAC enzyme, class I is ubiquitously expressed and class II is highly expressed in muscle, heart and brain.

  • In addition to deacetylating histones, HDACs also modify non-histone proteins such as the tumour suppressor p53 and heat shock protein 90 (HSP90), both of which are implicated in HD pathogenesis.

  • Compounds that inhibit these class I and II HDACs are in clinical trials for the treatment of many types of cancer. These drugs are currently being tested in preclinical trials using mouse models of polyglutamine repeat disease.

  • One HDAC inhibitor, phenylbutyrate, is in phase II clinical trials for HD, and alterations in blood biomarker expression after treatment look promising.

Abstract

During the past 5 years, gene expression studies in cell culture, animal models and in the brains of patients have shown that the perturbation of transcription frequently results in neuronal dysfunction in polyglutamine repeat diseases such as Huntington's disease. Histone deacetylases act as repressors of transcription through interactions with co-repressor complexes, which leads to chromatin remodelling. Aberrant interactions between polyglutamine proteins and regulators of transcription could be one mechanism by which transcriptional dysregulation occurs. Here, we discuss the potential therapeutic pathways through which histone deacetylase inhibitors might act to correct the aberrant transcription observed in Huntington's disease and other polyglutamine repeat diseases.

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Figure 1: Classes of histone deacetylase.
Figure 2: Potential mechanisms of transcriptional dysregulation in Huntington's disease.
Figure 3: Effects of HDAC inhibitors on non-histone acetylated proteins.

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Acknowledgements

Work in the author's laboratory is funded by the Wellcome Trust, Hereditary Disease Foundation, Huntington's Disease Society of America Coalition for the Cure and the HighQ Foundation.

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Correspondence to Gillian P. Bates.

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DATABASES

OMIM

Alzheimer's disease

DRPLA

Huntington's disease

Parkinson's disease

spinal and bulbar muscular atrophy

spinocerebellar ataxia type 3

FURTHER INFORMATION

Bates's laboratory

Huntington Project

Glossary

Histidine-aspartate charge-relay system

Histidine and aspartate residues coordinate the zinc cation and water molecule within the active site of the histone deacetylase enzyme that is required for the cleavage of an acetyl group from the substrate.

Nuclear co-repressor/silencing mediator of retinoid and thyroid hormone receptors

(N-CoR/SMRT). Co-repressors that interact with unliganded nuclear receptors and form repressor complexes that recruit histone deacetylases and other proteins to actively repress transcription.

Repressor element 1 transcription factor/neuron restrictive silencer factor

(REST/NSRF). REST/NRSF is a negative regulator of neuronal genes that contains a specific DNA response element in the promoter, the neuron restrictive silencing element (NRSE). REST/NRSF ensures the correct patterning of neuronal gene expression and the silencing of these genes in non-neuronal tissues.

Neuron restrictive silencing element

(NRSE). An NRSE is a 21 bp silencer element found in the promoters of neuronal genes to which REST/NRSF binds. It is also known as repressor element 1 (RE1).

RNA interference

(RNAi). A method by which double-stranded RNA that is encoded on an exogenous vector can be used to interfere with normal RNA processing, causing rapid degradation of the endogenous RNA and thereby precluding translation. This provides a simple way of studying the effects of the absence of a gene product in simple organisms and cells.

Dynein

A microtubule minus-end-directed motor protein that carries out retrograde transport from the cell surface to the centre of the cell. Dynein is a large molecule that complexes with dynactin to form direct and indirect associations with various cargoes.

Aggresome

An inclusion body of aggregated material, usually perinuclear, formed through dynein-dependent retrograde transport on microtubules.

Co-chaperones

Proteins associated with molecular chaperones that are necessary for full functional activity of the chaperone.

Small-molecule hydroxamates

Inhibitors containing hydroxamic acid residues are potent but reversible inhibitors of class I/II histone deacetylases (HDACs). They bind with high affinity and chelate the zinc cation at the bottom of the HDAC catalytic pocket.

Cyclic peptides

Histone deacetylase inhibitors that have epoxyketone (epoxide) moieties that could act by chemically binding to either the zinc cation or an amino acid in the active site.

Benzamides

A structurally diverse group of compounds that have an unknown mechanism of action. The diaminophenyl group present in these compounds is thought to be important for their inhibitory behaviour.

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Butler, R., Bates, G. Histone deacetylase inhibitors as therapeutics for polyglutamine disorders. Nat Rev Neurosci 7, 784–796 (2006). https://doi.org/10.1038/nrn1989

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