Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice

Authors

  • Hoon Ryu,

    1. Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford, and Departments of Neurology, Pathology and Psychiatry, Boston University School of Medicine, Boston, Massachusetts, USA
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  • Karen Smith,

    1. Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford, and Departments of Neurology, Pathology and Psychiatry, Boston University School of Medicine, Boston, Massachusetts, USA
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  • Sandra I. Camelo,

    1. Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford, and Departments of Neurology, Pathology and Psychiatry, Boston University School of Medicine, Boston, Massachusetts, USA
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  • Isabel Carreras,

    1. Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford, and Departments of Neurology, Pathology and Psychiatry, Boston University School of Medicine, Boston, Massachusetts, USA
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  • Junghee Lee,

    1. Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford, and Departments of Neurology, Pathology and Psychiatry, Boston University School of Medicine, Boston, Massachusetts, USA
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  • Antonio H. Iglesias,

    1. Laboratory of Transcriptional and Immune Regulation, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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  • Fernando Dangond,

    1. Laboratory of Transcriptional and Immune Regulation, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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  • Kerry A. Cormier,

    1. Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford, and Departments of Neurology, Pathology and Psychiatry, Boston University School of Medicine, Boston, Massachusetts, USA
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  • Merit E. Cudkowicz,

    1. Days Neuromuscular Laboratories, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
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  • Robert H. Brown Jr,

    1. Days Neuromuscular Laboratories, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
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  • Robert J. Ferrante

    1. Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford, and Departments of Neurology, Pathology and Psychiatry, Boston University School of Medicine, Boston, Massachusetts, USA
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Address correspondence and reprint requests to Robert J. Ferrante, PhD, MSc, Director, Experimental Neuropathology, Bedford VA Medical Center, Geriatric Research Education Clinical Center (GRECC) Unit, Building 18, 200 Springs Road, Bedford, MA 01730, USA.
E-mail: rjferr@bu.edu

Abstract

Multiple molecular defects trigger cell death in amyotrophic lateral sclerosis (ALS). Among these, altered transcriptional activity may perturb many cellular functions, leading to a cascade of secondary pathological effects. We showed that pharmacological treatment, using the histone deacetylase inhibitor sodium phenylbutyrate, significantly extended survival and improved both the clinical and neuropathological phenotypes in G93A transgenic ALS mice. Phenylbutyrate administration ameliorated histone hypoacetylation observed in G93A mice and induced expression of nuclear factor-κB (NF-κB) p50, the phosphorylated inhibitory subunit of NF-κB (pIκB) and beta cell lymphoma 2 (bcl-2), but reduced cytochrome c and caspase expression. Curcumin, an NF-κB inhibitor, and mutation of the NF-κB responsive element in the bcl-2 promoter, blocked butyrate-induced bcl-2 promoter activity. We provide evidence that the pharmacological induction of NF-κB-dependent transcription and bcl-2 gene expression is neuroprotective in ALS mice by inhibiting programmed cell death. Phenylbutyrate acts to phosphorylate IκB, translocating NF-κB p50 to the nucleus, or to directly acetylate NF-κB p50. NF-κB p50 transactivates bcl-2 gene expression. Up-regulated bcl-2 blocks cytochrome c release and subsequent caspase activation, slowing motor neuron death. These transcriptional and post-translational pathways ultimately promote motor neuron survival and ameliorate disease progression in ALS mice. Phenylbutyrate may therefore provide a novel therapeutic approach for the treatment of patients with ALS.

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