title: Polyglutamine-expanded ataxin-3 impairs long-term depression in Purkinje neurons of SCA3 transgenic mouse by inhibiting HAT and impairing histone acetylation.
abstract: 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 β4, 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 (HDAC). 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 β4 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 β4 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.
authors.affiliation: Department of Anesthesiology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan, ROC.
authors.forename: An-Hsun
authors.initials: AH
authors.lastname: Chou
authors.affiliation: Chang Gung University of Science and Technology, Tao-Yuan, Taiwan, ROC.
authors.forename: Ying-Ling
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Department of Physiology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, ROC.
authors.forename: Su-Huei
authors.initials: SH
authors.lastname: Hu
authors.affiliation: Department of Physiology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, ROC; Graduate Institute of Biomedical Sciences, Chang Gung University, Tao-Yuan, Taiwan, ROC.
authors.forename: Ya-Ming
authors.initials: YM
authors.lastname: Chang
authors.affiliation: Department of Physiology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, ROC; Neuroscience Research Center, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan, ROC; Healthy Aging Research Center, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan, ROC. Electronic address: hlwns@mail.cgu.edu.tw.
authors.forename: Hung-Li
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000067699:Ataxin-3; D020148:Butyric Acid / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D017827:Machado-Joseph Disease / Q000188:drug therapy / Q000503:physiopathology*; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides; D011689:Purkinje Cells / Q000187:drug effects / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D046509:Tissue Culture Techniques; D019680:Trinucleotide Repeat Expansion
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D020148:Butyric Acid; C097188:polyglutamine; D051548:Histone Acetyltransferases; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D006655:Histone Deacetylases
keywords: Cerebellar long-term depression; Histone acetylation; Histone acetyltransferase; Polyglutamine-expanded ataxin-3; Purkinje neuron; Spinocerebellar ataxia type 3