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Sodium Valproate Alleviates Neurodegeneration in SCA3/MJD via Suppressing Apoptosis and Rescuing the Hypoacetylation Levels of Histone H3 and H4

Spinocerebellar ataxia type 3 (SCA3) also known as Machado-Joseph Disease (MJD), is one of nine polyglutamine (polyQ) diseases caused by a CAG-trinucelotide repeat expansion within the coding sequence of the ATXN3 gene. There are no disease-modifying treatments for polyQ diseases. Recent studies sug...

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Detalles Bibliográficos
Autores principales: Yi, Jiping, Zhang, Li, Tang, Beisha, Han, Weiwei, Zhou, Yafang, Chen, Zhao, Jia, Dandan, Jiang, Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557284/
https://www.ncbi.nlm.nih.gov/pubmed/23382971
http://dx.doi.org/10.1371/journal.pone.0054792
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author Yi, Jiping
Zhang, Li
Tang, Beisha
Han, Weiwei
Zhou, Yafang
Chen, Zhao
Jia, Dandan
Jiang, Hong
author_facet Yi, Jiping
Zhang, Li
Tang, Beisha
Han, Weiwei
Zhou, Yafang
Chen, Zhao
Jia, Dandan
Jiang, Hong
author_sort Yi, Jiping
collection PubMed
description Spinocerebellar ataxia type 3 (SCA3) also known as Machado-Joseph Disease (MJD), is one of nine polyglutamine (polyQ) diseases caused by a CAG-trinucelotide repeat expansion within the coding sequence of the ATXN3 gene. There are no disease-modifying treatments for polyQ diseases. Recent studies suggest that an imbalance in histone acetylation may be a key process leading to transcriptional dysregulation in polyQ diseases. Because of this possible imbalance, the application of histone deacetylase (HDAC) inhibitors may be feasible for the treatment of polyQ diseases. To further explore the therapeutic potential of HDAC inhibitors, we constructed two independent preclinical trials with valproic acid (VPA), a promising therapeutic HDAC inhibitor, in both Drosophila and cell SCA3 models. We demonstrated that prolonged use of VPA at specific dose partly prevented eye depigmentation, alleviated climbing disability, and extended the average lifespan of SCA3/MJD transgenic Drosophila. We found that VPA could both increase the acetylation levels of histone H3 and histone H4 and reduce the early apoptotic rate of cells without inhibiting the aggregation of mutant ataxin-3 proteins in MJDtr-Q68- expressing cells. These results collectively support the premise that VPA is a promising therapeutic agent for the treatment of SCA3 and other polyQ diseases.
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spelling pubmed-35572842013-02-04 Sodium Valproate Alleviates Neurodegeneration in SCA3/MJD via Suppressing Apoptosis and Rescuing the Hypoacetylation Levels of Histone H3 and H4 Yi, Jiping Zhang, Li Tang, Beisha Han, Weiwei Zhou, Yafang Chen, Zhao Jia, Dandan Jiang, Hong PLoS One Research Article Spinocerebellar ataxia type 3 (SCA3) also known as Machado-Joseph Disease (MJD), is one of nine polyglutamine (polyQ) diseases caused by a CAG-trinucelotide repeat expansion within the coding sequence of the ATXN3 gene. There are no disease-modifying treatments for polyQ diseases. Recent studies suggest that an imbalance in histone acetylation may be a key process leading to transcriptional dysregulation in polyQ diseases. Because of this possible imbalance, the application of histone deacetylase (HDAC) inhibitors may be feasible for the treatment of polyQ diseases. To further explore the therapeutic potential of HDAC inhibitors, we constructed two independent preclinical trials with valproic acid (VPA), a promising therapeutic HDAC inhibitor, in both Drosophila and cell SCA3 models. We demonstrated that prolonged use of VPA at specific dose partly prevented eye depigmentation, alleviated climbing disability, and extended the average lifespan of SCA3/MJD transgenic Drosophila. We found that VPA could both increase the acetylation levels of histone H3 and histone H4 and reduce the early apoptotic rate of cells without inhibiting the aggregation of mutant ataxin-3 proteins in MJDtr-Q68- expressing cells. These results collectively support the premise that VPA is a promising therapeutic agent for the treatment of SCA3 and other polyQ diseases. Public Library of Science 2013-01-28 /pmc/articles/PMC3557284/ /pubmed/23382971 http://dx.doi.org/10.1371/journal.pone.0054792 Text en © 2013 Yi et al http://creativecommons.org/licenses/by/4.0/ 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 author and source are properly credited.
spellingShingle Research Article
Yi, Jiping
Zhang, Li
Tang, Beisha
Han, Weiwei
Zhou, Yafang
Chen, Zhao
Jia, Dandan
Jiang, Hong
Sodium Valproate Alleviates Neurodegeneration in SCA3/MJD via Suppressing Apoptosis and Rescuing the Hypoacetylation Levels of Histone H3 and H4
title Sodium Valproate Alleviates Neurodegeneration in SCA3/MJD via Suppressing Apoptosis and Rescuing the Hypoacetylation Levels of Histone H3 and H4
title_full Sodium Valproate Alleviates Neurodegeneration in SCA3/MJD via Suppressing Apoptosis and Rescuing the Hypoacetylation Levels of Histone H3 and H4
title_fullStr Sodium Valproate Alleviates Neurodegeneration in SCA3/MJD via Suppressing Apoptosis and Rescuing the Hypoacetylation Levels of Histone H3 and H4
title_full_unstemmed Sodium Valproate Alleviates Neurodegeneration in SCA3/MJD via Suppressing Apoptosis and Rescuing the Hypoacetylation Levels of Histone H3 and H4
title_short Sodium Valproate Alleviates Neurodegeneration in SCA3/MJD via Suppressing Apoptosis and Rescuing the Hypoacetylation Levels of Histone H3 and H4
title_sort sodium valproate alleviates neurodegeneration in sca3/mjd via suppressing apoptosis and rescuing the hypoacetylation levels of histone h3 and h4
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557284/
https://www.ncbi.nlm.nih.gov/pubmed/23382971
http://dx.doi.org/10.1371/journal.pone.0054792
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