Divalproex sodium modulates nuclear localization of ataxin‐3 and prevents cellular toxicity caused by expanded ataxin‐3

Wang, Zi‐Jian; Hanet, Aoife; Weishäupl, Daniel; Martins, Inês M.; Sowa, Anna; Rieß, Olaf; Schmidt, Thorsten

doi:10.1111/cns.12795

Cited by 13 publications

(17 citation statements)

References 69 publications

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“…Additionally, the motor symptoms were successfully ameliorated through sodium butyrate treatment [ 120 ]. Similar observations were made in SCA3 cell models, where the HDAC inhibitors valproic acid [ 178 ] as well as divalproex sodium [ 179 ] and sodium valproate [ 180 ] attenuated cellular toxicity induced by mutant ataxin-3. For SCA7, the HDAC inhibitor trichostatin A was tested in astrocytes expressing mutant ataxin-7 and was able to partially restore aberrant transcription of reelin, a factor involved in synaptic plasticity [ 181 ].…”

Section: Pharmacological Therapiessupporting

confidence: 60%

Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias

Buijsen¹,

Toonen²,

Gardiner

et al. 2019

Neurotherapeutics

101

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Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections. All ADCAs have progressive ataxia as their main clinical feature, frequently accompanied by dysarthria and oculomotor deficits. The most common spinocerebellar ataxias (SCAs) are 6 polyglutamine (polyQ) SCAs. These diseases are all caused by a CAG repeat expansion in the coding region of a gene. Currently, no curative treatment is available for any of the polyQ SCAs, but increasing knowledge on the genetics and the pathological mechanisms of these polyQ SCAs has provided promising therapeutic targets to potentially slow disease progression. Potential treatments can be divided into pharmacological and gene therapies that target the toxic downstream effects, gene therapies that target the polyQ SCA genes, and stem cell replacement therapies. Here, we will provide a review on the genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias.

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Section: Pharmacological Therapiessupporting

confidence: 60%

Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias

Buijsen¹,

Toonen²,

Gardiner

et al. 2019

Neurotherapeutics

101

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“…Consistent with the impairment of HAT and HDAC functions, several SCA3 models present a decrease of the bulk level of histones H3 and H4 acetylation (Yi et al, 2013;Chou et al, 2014;Lin et al, 2014;Wang et al, 2018). Moreover, downregulated LTD-associated genes in the Ataxin-3-Q79 mice have hypoacetylated promoters, and cerebellar protein extracts show a reduction of HAT activity, but not HDAC activity in vitro (Chou et al, 2014).…”

Section: Sca3mentioning

confidence: 75%

“…Treatment with the HDAC inhibitor (HDACi) sodium butyrate rescues H3 and H4 acetylation, expression of LTD-associated genes, LTD function of Purkinje cells and mice survival (Chou et al, 2008(Chou et al, , 2011(Chou et al, , 2014. Similarly, other HDACi, such as valproic acid or divalproex sodium, restore the histone acetylation level and prevent cytotoxicity in SCA3 cellular models (Yi et al, 2013;Lin et al, 2014;Wang et al, 2018) and extend the survival of a SCA3 fly model (Yi et al, 2013). At variance, valproic acid treatment of CMVMJD135 mice, which overexpress mutant ATXN3 cDNA, only mildly attenuates the motor phenotypes (Esteves et al, 2015).…”

Section: Sca3mentioning

confidence: 99%

“…However, the effects of HDACi treatments need to be interpreted with caution, since they have additional effects. For instance, valproate semisodium prevents the nuclear transport of mATXN3 in cellular models, hence reducing nuclear toxicity (Wang et al, 2018), and valproic acid-treated CMVMJD135 mice show an increased expression of the ER chaperon BIP/GRP78, which may enhance the folding capacity of the ER and provide neuroprotective effects (Esteves et al, 2015).…”

Section: Sca3mentioning

confidence: 99%

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Gene Deregulation and Underlying Mechanisms in Spinocerebellar Ataxias With Polyglutamine Expansion

2020

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Polyglutamine spinocerebellar ataxias (polyQ SCAs) include SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17 and constitute a group of adult onset neurodegenerative disorders caused by the expansion of a CAG repeat sequence located within the coding region of specific genes, which translates into polyglutamine tract in the corresponding proteins. PolyQ SCAs are characterized by degeneration of the cerebellum and its associated structures and lead to progressive ataxia and other diverse symptoms. In recent years, gene and epigenetic deregulations have been shown to play a critical role in the pathogenesis of polyQ SCAs. Here, we provide an overview of the functions of wild type and pathogenic polyQ SCA proteins in gene regulation, describe the extent and nature of gene expression changes and their pathological consequences in diseases, and discuss potential avenues to further investigate converging and distinct disease pathways and to develop therapeutic strategies.

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“…The HDAC inhibitor sodium butyrate ameliorates ataxic symptoms and improves survival rate of SCA3 transgenic mice ( Chou et al, 2011a ; Lin et al, 2014 ). Divalproex sodium, an HDAC inhibitor, rescues the hypoacetylation levels of histone H3 and attenuates cellular cytotoxicity in the SCA3 cell model ( Wang Z.J. et al, 2018 ).…”

Section: Spinocerebellar Ataxiamentioning

confidence: 99%

Transcriptional Dysregulation and Post-translational Modifications in Polyglutamine Diseases: From Pathogenesis to Potential Therapeutic Strategies

Xiang

Zhang

Dong

et al. 2018

Front. Mol. Neurosci.

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Polyglutamine (polyQ) diseases are hereditary neurodegenerative disorders caused by an abnormal expansion of a trinucleotide CAG repeat in the coding region of their respective associated genes. PolyQ diseases mainly display progressive degeneration of the brain and spinal cord. Nine polyQ diseases are known, including Huntington’s disease (HD), spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and six forms of spinocerebellar ataxia (SCA). HD is the best characterized polyQ disease. Many studies have reported that transcriptional dysregulation and post-translational disruptions, which may interact with each other, are central features of polyQ diseases. Post-translational modifications, such as the acetylation of histones, are closely associated with the regulation of the transcriptional activity. A number of groups have studied the interactions between the polyQ proteins and transcription factors. Pharmacological drugs or genetic manipulations aimed at correcting the dysregulation have been confirmed to be effective in the treatment of polyQ diseases in many animal and cellular models. For example, histone deaceylase inhibitors have been demonstrated to have beneficial effects in cases of HD, SBMA, DRPLA, and SCA3. In this review, we describe the transcriptional and post-translational dysregulation in polyQ diseases with special focus on HD, and we summarize and comment on potential treatment approaches targeting disruption of transcription and post-translation processes in these diseases.

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Divalproex sodium modulates nuclear localization of ataxin‐3 and prevents cellular toxicity caused by expanded ataxin‐3

Abstract: Our study provides novel insights into the mechanisms of action of divalproex sodium as a possible treatment for SCA3, beyond the known regulation of transcription.

Cited by 13 publications

References 69 publications

Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias

Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias

Gene Deregulation and Underlying Mechanisms in Spinocerebellar Ataxias With Polyglutamine Expansion

Transcriptional Dysregulation and Post-translational Modifications in Polyglutamine Diseases: From Pathogenesis to Potential Therapeutic Strategies

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