title: Valproic acid attenuates the suppression of acetyl histone H3 and CREB activity in an inducible cell model of Machado-Joseph disease.
abstract: Machado-Joseph disease (MJD) is caused by a (CAG)n trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract. This disease is considered the most common form of spinocerebellar ataxia (SCA). In the present study, we developed stable inducible cell lines (PC12Tet-On-Ataxin-3-Q28/84) expressing ataxin-3 with either normal or abnormal CAG repeats under doxycycline control. The expression of acetyl histone H3 and the induction of c-Fos in response to cAMP were strongly suppressed in cells expressing the protein with the expanded polyglutamine tract. Treatment with valproic acid, a histone deacetylase inhibitor (HDACi), attenuated mutant ataxin-3-induced cell toxicity and suppression of acetyl histone H3, phosphorylated cAMP-responsive element binding protein (p-CREB) as well as c-Fos expression. These results indicate that VPA can stimulate the up-regulation of gene transcription through hyperacetylation. Thus, VPA might have a therapeutic effect on MJD.
authors: Department of Huiqiao Building, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
authors: X P
authors: XP
authors: Lin
authors: Department of Neurological Intensive Care Unit, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors: L
authors: L
authors: Feng
authors: Department of Neurology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors: C G
authors: CG
authors: Xie
authors: Department of Neurology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors: D B
authors: DB
authors: Chen
authors: Department of Neurology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors: Z
authors: Z
authors: Pei
authors: Department of Neurology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors: X L
authors: XL
authors: Liang
authors: Department of Hyperbaric Oxygen Therapy, Guangzhou General Hospital of Guangzhou Military Area Command of Chinese PLA, Guangzhou, Guangdong Province, China.
authors: Q Y
authors: QY
authors: Xie
authors: Department of Neurology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China. Electronic address: linxiaopu@aliyun.com.
authors: X H
authors: XH
authors: Li
authors: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
authors: S Y
authors: SY
authors: Pan
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D050882:CREB-Binding Protein / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D010455:Peptides / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D016760:Proto-Oncogene Proteins c-fos; D012097:Repressor Proteins; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D014635:Valproic Acid; D020932:Nerve Growth Factor; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C092341:ATXN3 protein, human; D000067699:Ataxin-3
keywords: CREB; HDAC inhibitor; MJD; Valproic acid