TY - JOUR
T1 - HDAC inhibitor sodium butyrate reverses transcriptional downregulation and ameliorates ataxic symptoms in a transgenic mouse model of SCA3
AU - Chou, An Hsun
AU - Chen, Si Ying
AU - Yeh, Tu Hsueh
AU - Weng, Yi Hsin
AU - Wang, Hung Li
PY - 2011/2
Y1 - 2011/2
N2 - 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.
AB - 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.
KW - Ataxin-3
KW - Cerebellum
KW - Histone deacetylase
KW - Polyglutamine-expanded ataxin-3
KW - SCA3 transgenic mice
KW - Spinocerebellar ataxia type 3
UR - http://www.scopus.com/inward/record.url?scp=78650613146&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78650613146&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2010.10.019
DO - 10.1016/j.nbd.2010.10.019
M3 - Article
C2 - 21047555
AN - SCOPUS:78650613146
SN - 0969-9961
VL - 41
SP - 481
EP - 488
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 2
ER -