Butler R, Bates GP. Histone deacetylase inhibitors as therapeutics for polyglutamine disorders. Nat Rev Neurosci 7: 784-796

King's College London School of Medicine, Department of Medical and Molecular Genetics, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK.
Nature reviews Neuroscience (Impact Factor: 31.43). 11/2006; 7(10):784-96. DOI: 10.1038/nrn1989
Source: PubMed


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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    • "Thereby, aggregates in the nucleus (nuclear inclusions) but also in the cytoplasm, e.g. neuropils, are formed [4] [5]. The mutant huntingtin can undergo different conformations including aberrantly folded monomeric forms, a wide-range of oligomeric species, fibril states, and larger insoluble aggregates [6]. "
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    ABSTRACT: Huntington's disease is a hereditary movement disorder that is characterized by progressive neuronal cell death mainly in the cortex and striatum of the brain. It is caused by an unstable CAG repeat extension in the first exon of the IT-15 gene which encodes a protein called huntingtin (Htt). The trinucleotide expansion translates into an elongated polyglutamine (polyQ) stretch. A polyQ length of more than 35 glutamine residues is associated with the appearance of huntingtin aggregates and the development of the disease. The process of aggregation is not fully understood but its inhibition and its modulation provide an insight into the mechanisms leading to aggregate formation which might be a target for the treatment of the disease. Using CFP-and YFP-tagged huntingtin exon 1 fragments we established a cellular model that visualizes the process of huntingtin aggregation and in which the aggregates could be specifically detected by FRET microscopy (acceptor photobleaching and fluorescence lifetime microscopy). The time course of the aggregation process was investigated by image analysis. 1. Role of huntingtin aggregates in Huntington's disease Huntington's disease (HD) (OMIM 143100) is a autosomal dominant, age-at-onset, progressive neurodegenerative disorder caused by an expanded (CAG)n repeat in the exon 1 of the huntingtin gene IT-15 located on chromosome 4 [1]. The expansion above the normal range of 6–35 CAG repeats leads to an elongated poly-glutamine (polyQ) tract that causes misfolding and aberrant protein-protein interactions thereby conferring a multifaceted toxic gain of function to the widely expressed huntingtin protein. The age of onset is most critically determined by and inversely correlated with the length of the expanded CAG repeat. HD is characterized by neurodegeneration and formation of neuronal intranuclear and cytoplasmic accumulation of aggregated mutant huntingtin, particularly in the striatum and cortex but also extended to other brain regions. The resulting clinical phenotype summarizes progressive movement dysfunction, cognitive impairments, psychiatric symptoms, and ultimately death. Currently, no cure or therapy for delaying HD-associated symptoms is available. HD belongs to a set of ten, dominantly inherited neurodegenerative disorders, the polyglutamine (polyQ) diseases, each caused by expanded polyglutamine (polyQ) tracts in otherwise unrelated proteins [2, 3]. HD pathophysiological processes are multiple, complex and variable including impairments of transcription, axonal transport, ubiquitin proteasome system and of mitochondrial function. A key feature in HD pathogenesis is the poly(Q) dependent self-association and aggregation of mutant huntingtin proteins and of N-terminal toxic htt peptides generated by proteolytic cleavage. Thereby, aggregates in the nucleus (nuclear inclusions) but also in the cytoplasm, e.g. neuropils, are formed [4, 5]. The mutant huntingtin can undergo different conformations including aberrantly folded monomeric forms, a wide-range of oligomeric species, fibril states, and larger insoluble aggregates [6]. The role of mutant huntingtin aggregation in the pathogenesis of HD as well as the toxic impact of different forms of mutant Htt is intensely discussed. Aggregation-mediated sequestration of proteins with essential cellular functions could be harmful to the cell, whereas a protective mechanism resulting from sequestration of the toxic Htt moiety or other cellular proteins which stimulate mutant Htt clearance would be beneficial. Furthermore, different structures of mHtt aggregates seem to determine the nature of proteins being trapped. Thus, the resulting toxic effects are also driven by whichever cell-specific proteins are present. Altogether, this may account for selective dysfunction and degeneration in HD. As a consequence, the modulation of mHtt aggregation could have beneficial effects on overall toxicity or specific cellular pathways deregulated in HD. This has been successfully shown by the interaction of a specific intrabody with mutant huntingtin leading to increased ubiquitination and clearance of cytoplasmic mHtt as well as a subsequent prevention of mHtt accumulation in neuronal processes and a reduced neurotoxicity [7]. Modulation of the mHtt aggregation process by shifting the equilibrium toward soluble huntingtin was achieved by reducing the level of histone deacetylase HDAC4. The resulted delay in cytoplasmic mHtt aggregation alleviated disease progression and led to improvement of neurological phenotypes in an HD mouse model. These data clearly indicate that cytoplasmic aggregation mechanisms contribute to HD-related neurodegenerative phenotypes [8]. Elucidating the relationship of different forms of mHtt aggregates to toxicity and to disease progression is thus an important step in the pathway to therapeutic interventions. In order to study HD pathomechanisms considerable effort has been invested in the development of in vitro and in vivo model systems [6, 9]. One way to study the fate of proteins in living cells is to use fluorescent protein (FP) fusions. Proteins tagged with FPs often retain their biochemical properties and allow the functional analysis of proteins in living cells. In combination with microscopic techniques FP tags are ideally suited to analyse spatio-temporal processes such Microscopy: advances in scientific research and education (A. Méndez-Vilas, Ed.)
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    • "Changes in DNMT gene expression as well as DNA methylation have also been shown to take place in psychiatric diseases such as schizophrenia (Tremolizzo et al., 2002; Veldic et al., 2005). Observations have also been made that involve other epigenetic mechanisms, such as histone acetylation that has been shown to be implicated in numerous brain activities such as memory formation (Fischer et al., 2007; LaPlant et al., 2010); and neurodegenerative diseases such as Huntington’s disease (Butler and Bates, 2006). Thus, strong evidence supports a critical role for epigenetic regulation of CNS activity in adult animals. "
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    ABSTRACT: Neuropathic pain is associated with hyperexcitability and intrinsic firing of dorsal root ganglia (DRG) neurons. These phenotypical changes can be long lasting, potentially spanning the entire life of animal models, and depend on altered expression of numerous proteins, including many ion channels. Yet, how DRGs maintain long-term changes in protein expression in neuropathic conditions remains unclear. DNA methylation is a well-known mechanism of epigenetic control of gene expression and is achieved by the action of three enzymes: DNA methyltransferase (DNMT) 1, 3a, and 3b, which have been studied primarily during development. We first performed immunohistochemical analysis to assess whether these enzymes are expressed in adult rat DRGs (L4–5) and found that DNMT1 is expressed in both glia and neurons, DNMT3a is preferentially expressed in glia and DNMT3b is preferentially expressed in neurons. A rat model of neuropathic pain was then used to determine whether nerve injury may induce epigenetic changes in DRGs at multiple time points after pain onset. Real-time RT PCR analysis revealed robust and time-dependent changes in DNMT transcript expression in ipsilateral DRGs from spared nerve injury (SNI) but not sham rats. Interestingly, DNMT3b transcript showed a robust upregulation that appeared already 1 week after surgery and persisted at 4 weeks (our endpoint); in contrast, DNMT1 and DNMT3a transcripts showed only moderate upregulation that was transient and did not appear until the second week. We suggest that DNMT regulation in adult DRGs may be a contributor to the pain phenotype and merits further study.
    Full-text · Article · Aug 2014 · Frontiers in Cellular Neuroscience
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    • "The acetylation of specific lysine residues influences the activity of many proteins including histones and this process has been shown to be a central mechanism controlling gene expression and cell signaling events. There is an increasing body of evidence to suggest that chromatin structure and epigenetic regulation are major players in the pathology of many diseases including neurodegenerative disorders [1]. Reversible lysine acetylation is controlled by the antagonistic commitment of two enzymes families: the histone acetyltransferases (HATs) and the histone deacetylases (HDACs) [2]. "
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    ABSTRACT: Reversible protein acetylation provides a central mechanism for controlling gene expression and cellular signaling events. It is governed by the antagonistic commitment of two enzymes families: the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). HDAC4, like its class IIa counterparts, is a potent transcriptional repressor through interactions with tissue specific transcription factors via its N-terminal domain. Whilst the lysine deacetylase activity of the class IIa HDACs is much less potent than that of the class I enzymes, HDAC4 has been reported to influence protein deacetylation through its interaction with HDAC3. To investigate the influence of HDAC4 on protein acetylation we employed the immunoaffinity-based AcetylScan proteomic method. We identified many proteins known to be modified by acetylation, but found that the absence of HDAC4 had no effect on the acetylation profile of the murine neonate brain. This is consistent with the biochemical data suggesting that HDAC4 may not function as a lysine deacetylase, but these in vivo data do not support the previous report showing that the enzymatic activity of HDAC3 might be modified by its interaction with HDAC4. To complement this work, we used Affymetrix arrays to investigate the effect of HDAC4 knock-out on the transcriptional profile of the postnatal murine brain. There was no effect on global transcription, consistent with the absence of a differential histone acetylation profile. Validation of the array data by Taq-man qPCR indicated that only protamine 1 and Igfbp6 mRNA levels were increased by more than one-fold and only Calml4 was decreased. The lack of a major effect on the transcriptional profile is consistent with the cytoplasmic location of HDAC4 in the P3 murine brain.
    Full-text · Article · Nov 2013 · PLoS ONE
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