Polyglutamine-expanded ataxin-3 impairs long-term depression in Purkinje neurons of SCA3 transgenic mouse by inhibiting HAT and impairing histone acetylation

被引：26

作者：

Chou, An-Hsun ^{[1
]}

Chen, Ying-Ling ^{[2
]}

Hu, Su-Huei ^{[3
]}

Chang, Ya-Ming ^{[3
,4
]}

Wang, Hung-Li ^{[3
,5
,6
]}

机构：

[1] Chang Gung Mem Hosp, Dept Anesthesiol, Taoyuan, Taiwan

[2] Chang Gung Univ Sci & Technol, Taoyuan, Taiwan

[3] Chang Gung Univ, Coll Med, Dept Physiol, Taoyuan, Taiwan

[4] Chang Gung Univ, Grad Inst Biomed Sci, Taoyuan, Taiwan

[5] Chang Gung Mem Hosp, Neurosci Res Ctr, Taoyuan, Taiwan

[6] Chang Gung Univ, Hlth Aging Res Ctr, Taoyuan, Taiwan

来源：

BRAIN RESEARCH | 2014年 / 1583卷

关键词：

Spinocerebellar ataxia type 3; Polyglutamine-expanded ataxin-3; Purkinje neuron; Cerebellar long-term depression; Histone acetylation; Histone acetyltransferase; MACHADO-JOSEPH-DISEASE; CAUSES CEREBELLAR DYSFUNCTION; HUNTINGTONS-DISEASE; TRANSCRIPTIONAL DYSREGULATION; MODEL; MECHANISMS; PLASTICITY; DISORDERS; INDUCTION; CIRCUITRY;

D O I：

10.1016/j.brainres.2014.08.019

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Our previous study using a transgenic mouse model of spinocerebellar ataxia type 3 (SCA3) reported that disease-causing ataxin-3-Q79 caused cerebellar malfunction by inducing transcriptional downregulation. Long-term depression (LTD) of parallel fiber-Purkinje neuron glutamatergic transmission is believed to be a cellular mechanism for motor learning and motor coordination in the cerebellum. Downregulated mRNA expression of calcineurin B, IP3-R1, myosin Va and PLC beta 4, which are required for the induction of cerebellar LTD, led to an impairment of LTD induction in Purkinje neurons of SCA3 transgenic mouse. Our study suggested that ataxin-3-Q79 caused hypoacetylation of cerebellar histone H3 or H4 by inhibiting the activity of histone acetyltransferase (HAT) without affecting the activity of histone deacetylase (HDAq. Consistent with the hypothesis that hypoacetylated H3 or H4 histone associated with promoter regions of downregulated genes is the molecular mechanism underlying ataxin-3-Q79-induced transcriptional repression, chromatin immunoprecipitation-quantitative real-time PCR analysis showed hypoacetylation of H3 or H4 histone associated with the proximal promoter of downregulated calcineurin B, IP3-R1, myosin Va or PLC beta 4 gene in the cerebellum of SCA3 mouse. HDAC inhibitor sodium butyrate reversed ataxin-3-Q79-induced hypoacetylation of histone H3 or H4 associated with the proximal promoter of calcineurin B, IP3-R1, myosin Va or PLC beta 4 gene. Sodium butyrate also prevented ataxin-3-Q79-induced impairment of LTD induction in Purkinje neurons of SCA3 mice. Our results suggest that polyglutamine-expanded ataxin-3-Q79 impairs HAT activity, leading to histone hypoacetylation, downregulated expression of cerebellar genes required for LTD induction and impaired induction of cerebellar LTD in the SCA3 transgenic mouse. (C) 2014 Elsevier B.V. All rights reserved.

引用

页码：220 / 229

页数：10

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