HDAC inhibitor sodium butyrate reverses transcriptional downregulation and ameliorates ataxic symptoms in a transgenic mouse model of SCA3

Chou, An Hsun; Chen, Si Ying; Yeh, Tu Hsueh; Weng, Yueh-Hsuan; Wang, Hung Li

doi:10.1016/j.nbd.2010.10.019

Cited by 89 publications

(94 citation statements)

References 34 publications

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“…The greater abundance of polyQ ATXN7 may be responsible for the increase in NI-containing cells following TSA treatment; however, further investigation will be required to elucidate the relationship between these two events. Interestingly, experiments in other polyglutamine expansion disorder models have indicated that the formation of NIs is not affected by treatment with SAHA (40), nicotinamide (41), or sodium butyrate (40,42). The TSA-dependent increase in NI formation and coinciding restoration of H2B monoubiquitination levels may suggest that the mechanism for TSA-dependent rescue of RELN expression involves the sequestration of polyQ ATXN7 into NIs, away from affected promoters in the TSA-treated cells.…”

Section: Discussionmentioning

confidence: 99%

Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

McCullough

Dent

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder that results from polyglutamine expansion of the ataxin-7 (ATXN7) protein. Remarkably, although mutant ATXN7 is expressed throughout the body, pathology is restricted primarily to the cerebellum and retina. One major goal has been to identify factors that contribute to the tissue specificity of SCA7. Here we describe the development and use of a human astrocyte cell culture model to identify reelin, a factor intimately involved in the development and maintenance of Purkinje cells and the cerebellum as a whole, as an ATXN7 target gene. We found that polyglutamine expansion decreased ATXN7 occupancy, which correlated with increased levels of histone H2B monoubiquitination, at the reelin promoter. Treatment with trichostatin A, but not other histone deacetylase inhibitors, partially restored reelin transcription and promoted the accumulation of mutant ATXN7 into nuclear inclusions. Our findings suggest that reelin could be a previously unknown factor involved in the tissue specificity of SCA7 and that trichostatin A may ameliorate deleterious effects of the mutant ATXN7 protein by promoting its sequestration away from promoters into nuclear inclusions.chromatin | SAGA complex | histone modification A s a member of the polyglutamine expansion disorder family, Spinocerebellar ataxia type 7 (SCA7) is an autosomaldominant hereditary disease characterized by cerebellar and retinal degeneration eventually leading to death (1). Although the ataxin-7 (ATXN7) protein is expressed throughout the body, pathology is localized primarily within the cerebellum and retina. Cerebellar Purkinje cell (PC) degeneration is an integral step in the development and progression of SCA7 and has been observed in several independent transgenic mouse models of the disease (2-5); however, increasing evidence indicates that glial cell dysfunction contributes significantly to polyglutamine expansion disorder pathology (2, 6, 7). Interestingly, two distinct SCA7 mouse models exhibit non-cell-autonomous neurodegeneration (2, 4). Of these, the model used by Custer et al. (2) demonstrates that astrocyte-specific expression of polyQ ATXN7, via the Gfa2 promoter (8), results in PC degeneration and the onset of SCA7 symptoms. Astrocytes play a crucial role in the regulation of synaptic formation and function by ensheathing axon-dendrite connections to form a structure known as the tripartite synapse (9). This intimate interaction allows astrocytes to modulate synaptic function through the release of chemical messengers and the regulation of neurotransmitter and ion concentration within the synapse (9-11). The identification of tissue specificity factors and characterization of associated molecular mechanisms involved in their deregulation will facilitate a more comprehensive understanding of disease-associated events and advance efforts to develop effective treatments.The ATXN7 protein is an integral subunit of GCN5 (general control of amino acid synthesis-5; KAT2A)...

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Section: Discussionmentioning

confidence: 99%

Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

McCullough

Dent

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…2) Model 4 (and predictable model 1) has transcriptional dysregulation in the cerebellum [35], which is reversible with sodium butyrate [52].…”

Section: Discussionmentioning

confidence: 99%

Mouse Models of Spinocerebellar Ataxia Type 3 (Machado-Joseph Disease)

Gould

2012

Neurotherapeutics

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“…The toxicity of causative gene products in MJD and other polyglutamine diseases has been proposed to be influenced not only by the polyglutamine stretch but also by the posttranslational modification of amino acid residues outside the polyglutamine stretch, including phosphorylation Tao et al, 2008;Mueller et al, 2009), acetylation (Li et al, 2002Evert et al, 2006;Chou et al, 2011), ubiquitination (Matsumoto et al, 2004;Jana et al, 2005;de Pril et al, 2007), and sumoylation (Ueda et al, 2002;Shen et al, 2005). These modifications might result in aberrant interactions with other proteins or modification of the properties of causative proteins, including the stability or tendency to form toxic structures.…”

Section: Toxicity Of the Polyglutamine Stretchmentioning

confidence: 99%

“…Moreover, it was shown that the use of several reagents that increase transcription reduce the toxicity of expanded polyglutamine (Steffan et al, 2001;Ferrante et al, 2003Ferrante et al, , 2004Hockly et al, 2003;Gardian et al, 2005;Shimohata et al, 2005). Recently, it was shown that regulation of transcriptional activity through an inhibition of histone hypoacetylation (Chou et al, 2011) might be a promising therapeutic intervention for MJD. Histone acetylation, which is controlled by histone acetyltransferase and histone deacetylase (HDAC), plays an important role in regulating transcriptional activity (Kurdistani et al, 2004).…”

Section: Targeting Transcriptional Dysfunctionmentioning

confidence: 99%

“…The H3 and H4 histones were hypoacetylated in the cerebellum of MJD transgenic mice, which displayed transcription downregulation and ataxic symptoms. Daily administration of a HDAC inhibitor (sodium butyrate) reversed histone hypoacetylation and transcriptional downregulation in the cerebellum of the MJD transgenic mice, delaying the onset of ataxic symptoms, ameliorated the neurological phenotype and improved the survival rate of the mice (Chou et al, 2011).…”

Section: Targeting Transcriptional Dysfunctionmentioning

confidence: 99%

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