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      Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy

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          Abstract

          Histone acetylation plays an important role in regulation of transcription in eukaryotic cells by promoting a more relaxed chromatin structure necessary for transcriptional activation. Histone deacetylases (HDACs) remove acetyl groups and suppress gene expression. HDAC inhibitors (HDACIs) are a group of small molecules that promote gene transcription by chromatin remodeling and have been extensively studied as potential drugs for treating of spinal muscular atrophy. Various drugs in this class have been studied with regard to their efficacy in increasing the expression of survival of motor neuron (SMN) protein. In this review, we discuss the current literature on this topic and summarize the findings of the main studies in this field.

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          Histone deacetylase 6 plays a role as a distinct regulator of diverse cellular processes.

          Yingxiu Li, Donghee Shin, So Hee Kwon (2013)
          Histone deacetylase (HDAC) 6 is the best-characterized class IIb deacetylase that regulates many important biological processes via the formation of complexes with its partner proteins. HDAC6 is important both for cytoplasmic and nuclear functions. Unlike other deacetylases, HDAC6 has unique substrate specificity for nonhistone proteins. Such diverse functions of HDAC6 suggest that it serves a potential therapeutic target for the treatment of a wide range of diseases. This therapeutic interest in HDAC6 stems from the observation that HDAC6 may be overexpressed or deregulated in various cancers, neurodegenerative diseases and inflammatory disorders. Despite extensive efforts, however, very few HDAC6-selective inhibitors have been identified and the precise structural determinants remain undefined. Future efforts aiming to better define the structure and function of HDAC6 should provide the basis for the discovery of novel effective inhibitors. In this review, we focus on recent studies that highlight the importance of HDAC6-mediated biological processes, disease mechanisms and HDAC6-selective inhibitors. © 2012 The Authors Journal compilation © 2012 FEBS.
          Article 0 comments Cited 105 times – based on 0 reviews     Review now
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            Sirtuins at a glance.

            Takashi Nakagawa, Leonard Guarente (2011)
            Article 0 comments Cited 86 times – based on 0 reviews     Review now
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              Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy.

              E Hahnen, I Blümcke, Florian Siebzehnrubl … (2003)
              Proximal spinal muscular atrophy (SMA) is a common neuromuscular disorder causing infant death in half of all patients. Homozygous absence of the survival motor neuron gene (SMN1) is the primary cause of SMA, while SMA severity is mainly determined by the number of SMN2 copies. One SMN2 copy produces only about 10% of full-length protein identical to SMN1, whereas the majority of SMN2 transcripts is aberrantly spliced due to a silent mutation within an exonic splicing enhancer in exon 7. However, correct splicing can be restored by over-expression of the SR-like splicing factor Htra2-beta 1. We show that in fibroblast cultures derived from SMA patients treated with therapeutic doses (0.5-500 microM) of valproic acid (VPA), the level of full-length SMN2 mRNA/protein increased 2- to 4-fold. Importantly, this up-regulation of SMN could be most likely attributed to increased levels of Htra2-beta 1 which facilitates the correct splicing of SMN2 RNA as well as to an SMN gene transcription activation. Especially at low VPA concentrations, the restored SMN level depended on the number of SMN2 copies. Moreover, VPA was able to increase SMN protein levels through transcription activation in organotypic hippocampal brain slices from rats. Finally, VPA also increased the expression of further SR proteins, which may have important implications for other disorders affected by alternative splicing. Since VPA is a drug highly successfully used in long-term epilepsy therapy, our findings open the exciting perspective for a first causal therapy of an inherited disease by elevating the SMN2 transcription level and restoring its correct splicing.
              Article 0 comments Cited 60 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Genet Mol Biol
                Journal ID (iso-abbrev): Genet. Mol. Biol
                Journal ID (publisher-id): GMB
                Title: Genetics and Molecular Biology
                Publisher: Sociedade Brasileira de Genética (Ribeirão Preto, SP, Brazil )
                ISSN (Print): 1415-4757
                ISSN (Electronic): 1678-4685
                Publication date (Print): September 2013
                Publication date (Electronic): 30 August 2013
                Volume: 36
                Issue: 3
                Pages: 299-307
                Affiliations
                [1 ]Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia.
                [2 ]Department of Pediatrics, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia.
                Author notes
                Send correspondence to Teguh Haryo Sasongko. Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia, USM Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia. E-mail: teguhharyosasongko@ 123456yahoo.com , teguhhs@ 123456kk.usm.my .
                Article
                Publisher ID: 2012-380
                DOI: 10.1590/S1415-47572013000300001
                PMC ID: 3795173
                PubMed ID: 24130434
                SO-VID: 2b6d5f1d-bebd-41fe-a6be-ca8f63c7a73e
                Copyright © Copyright © 2013, Sociedade Brasileira de Genética.
                License:

                License information: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 01 January 2013
                Date accepted : 20 June 2013
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Molecular biology
                Keywords: hdaci,molecular therapy,spinal muscular atrophy
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: hdaci, molecular therapy, spinal muscular atrophy

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