title: Sodium valproate alleviates neurodegeneration in SCA3/MJD via suppressing apoptosis and rescuing the hypoacetylation levels of histone H3 and H4.
abstract: 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.
authors: Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
authors: Jiping
authors: J
authors: Yi
authors: Li
authors: L
authors: Zhang
authors: Beisha
authors: B
authors: Tang
authors: Weiwei
authors: W
authors: Han
authors: Yafang
authors: Y
authors: Zhou
authors: Zhao
authors: Z
authors: Chen
authors: Dandan
authors: D
authors: Jia
authors: Hong
authors: H
authors: Jiang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D042622:DNA Repeat Expansion; D004330:Drosophila; D005123:Eye / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008017:Life Expectancy; D017827:Machado-Joseph Disease / Q000378:metabolism*; D009154:Mutation; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010858:Pigmentation / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D010455:Peptides; C097188:polyglutamine; D014635:Valproic Acid
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