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

An Hsun Chou, Si Ying Chen, Tu Hsueh Yeh, Yi Hsin Weng, Hung Li Wang

研究成果: 雜誌貢獻文章

70 引文 斯高帕斯(Scopus)

摘要

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disease caused by polyglutamine-expanded ataxin-3. Previously, we prepared a SCA3 animal model by generating transgenic mice expressing disease-causing ataxin-3-Q79. Mutant ataxin-3-Q79 caused cerebellar malfunction of SCA3 transgenic mice by downregulating cerebellar mRNA expressions of proteins involved in synaptic transmission, signal transduction or regulating neuronal survival/differentiation. Histone acetylation, which is controlled by histone acetyltransferase and histone deacetylase (HDAC), plays an important role in regulating transcriptional activity. In the present study, we tested the hypothesis that ataxin-3-Q79 causes cerebellar transcriptional downregulation by inducing histone hypoacetylation and that HDAC inhibitor sodium butyrate (SB) alleviates ataxic symptoms of SCA3 transgenic mice by reversing ataxin-3-Q79-induced histone hypoacetylation and transcriptional repression. Compared to wild-type mice, H3 and H4 histones were hypoacetylated in the cerebellum of 6- to 8-month-old ataxin-3-Q79 transgenic mice, which displayed transcriptional downregulation and ataxic symptoms. Daily intraperitoneal administration of SB significantly reversed ataxin-3-Q79-induced histone hypoacetylation and transcriptional downregulation in the cerebellum of SCA3 transgenic mice. SB treatment also delayed the onset of ataxic symptoms, ameliorated neurological phenotypes and improved the survival rate of ataxin-3-Q79 transgenic mice. The present study provides the evidence that mutant ataxin-3-Q79 causes cerebellar transcriptional repression and ataxic symptoms of SCA3 transgenic mice by inducing hypoacetylation of histones H3 and H4. Our results suggest that sodium butyrate might be a promising therapeutic agent for SCA3.
原文英語
頁(從 - 到)481-488
頁數8
期刊Neurobiology of Disease
41
發行號2
DOIs
出版狀態已發佈 - 二月 2011
對外發佈Yes

ASJC Scopus subject areas

  • Neurology

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