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.

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

“…This compound (or its salt) has been proven to delay the disease onset, reduce neurological deficits, and/or prolong survival in several models of neurodegenerative diseases, including HD, SBMA, and ALS . In MJD/SCA3, VPA (a multitarget compound) was reported to alleviate neurodegeneration in a Drosophila model of the disease and attenuate mutant ATXN3‐induced cell toxicity in a human neuronal cell model, while only mild effects in the CMVMJD135 mouse model . In contrast, safety and efficacy of VPA was suggested in a clinical trial with MJD/SCA3 patients (see Section ) .…”

Divalproex sodium modulates nuclear localization of ataxin‐3 and prevents cellular toxicity caused by expanded ataxin‐3

“…Emerging data indicate HDAC inhibitors as potential therapeutic compounds for the treatment of neurodegenerative diseases such as SCA3, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis . However, the exact mechanism of action of HDAC inhibitors is still widely unknown.…”

“…Emerging data indicate HDAC inhibitors as potential therapeutic compounds for the treatment of neurodegenerative diseases such as SCA3, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] However, the exact mechanism of action of HDAC inhibitors is still widely unknown. 36 Phenylbutyrate has already entered a phase II clinical trial for the treatment of HD.…”

“…25 Recent studies show that VPA alleviates neurodegeneration and extends the life span of a Drosophila SCA3 model 35 and that VPA rescues hypoacetylated H3 and H4 levels in SCA3 cell models. 20 Valproic acid is found to ameliorate dopaminergic neurodegeneration and prolongs the life span in Caenorhabditis elegans. 37,38 Besides, safety and efficacy of VPA has been tested in patients with SCA3/MJD.…”

Deep cerebellar stimulation reduces ataxic motor symptoms in the shaker rat

“…Therapeutic approaches vary, 4 but they typically fail to sufficiently alleviate symptoms. [5][6][7][8][9] Most degenerative ataxias feature Purkinje cell loss, 10,11 resulting in modified inputs to the deep cerebellar nuclei; thus, neuromodulation targeting these deep cerebellar nuclei may succeed in numerous DCAs.…”