Valproic acid attenuates the suppression of acetyl histone H3 and CREB activity in an inducible cell model of Machado-Joseph disease

X P Lin; L Feng; C G Xie; D B Chen; Z Pei; X L Liang; Q Y Xie; X H Li; S Y Pan

doi:10.1016/j.ijdevneu.2014.07.004

Valproic acid attenuates the suppression of acetyl histone H3 and CREB activity in an inducible cell model of Machado-Joseph disease

Int J Dev Neurosci. 2014 Nov:38:17-22. doi: 10.1016/j.ijdevneu.2014.07.004. Epub 2014 Jul 25.

Authors

X P Lin¹, L Feng², C G Xie³, D B Chen³, Z Pei³, X L Liang³, Q Y Xie⁴, X H Li⁵, S Y Pan⁶

Affiliations

¹ Department of Huiqiao Building, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
² Department of Neurological Intensive Care Unit, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
³ Department of Neurology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
⁴ Department of Hyperbaric Oxygen Therapy, Guangzhou General Hospital of Guangzhou Military Area Command of Chinese PLA, Guangzhou, Guangdong Province, China.
⁵ Department of Neurology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China. Electronic address: linxiaopu@aliyun.com.
⁶ Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.

PMID: 25068645
DOI: 10.1016/j.ijdevneu.2014.07.004

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.

Keywords: CREB; HDAC inhibitor; MJD; Valproic acid.

MeSH terms

Animals
Ataxin-3
CREB-Binding Protein / metabolism*
Cell Differentiation / drug effects
Cell Differentiation / physiology
Cell Proliferation / drug effects
Cell Proliferation / genetics
Cyclic AMP / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology*
Gene Expression Regulation / drug effects*
Gene Expression Regulation / genetics
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Histones / metabolism*
Humans
Nerve Growth Factor / pharmacology
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
PC12 Cells
Peptides / metabolism
Proto-Oncogene Proteins c-fos / metabolism
Rats
Repressor Proteins / genetics
Repressor Proteins / metabolism
Transfection
Trinucleotide Repeat Expansion / genetics
Valproic Acid / pharmacology*

Substances

Enzyme Inhibitors
Histones
Nerve Tissue Proteins
Nuclear Proteins
Peptides
Proto-Oncogene Proteins c-fos
Repressor Proteins
Green Fluorescent Proteins
polyglutamine
Valproic Acid
Nerve Growth Factor
Cyclic AMP
CREB-Binding Protein
ATXN3 protein, human
Ataxin-3