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The Journal of Neuroscience, October 15, 2003, 23(28):9418-9427
Previous Article | Next Article
Cellular/Molecular
Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington's Disease Mice
Robert J. Ferrante,1,2 James K. Kubilus,1,2 Junghee Lee,1,2 Hoon Ryu,1,2 Ayshe Beesen,5,6 Birgit Zucker,5,6 Karen Smith,1,2 Neil W. Kowall,1,2 Rajiv R. Ratan,3,4 Ruth Luthi-Carter,5,6 andSteven M. Hersch5,6 1Geriatric Research Education and Clinical Center, Bedford Veterans Affairs Medical Center, Bedford, Massachusetts 01730, 2Departments of Neurology, Pathology, and Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, 3Department of Neurology and Program in Neuroscience, Harvard Medical School, 4Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts 02115, 5Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, and 6Center for Aging, Genetics, and Neurodegeneration, Massachusetts General Hospital, Charlestown, Massachusetts 02129
The precise cause of neuronal death in Huntington's disease (HD) is unknown. Although no single specific protein-protein interaction of mutant huntingtin has emerged as the pathologic trigger, transcriptional dysfunction may contribute to the neurodegeneration observed in HD. Pharmacological treatment using the histone deacetylase inhibitor sodium butyrate to modulate transcription significantly extended survival in a dose-dependent manner, improved body weight and motor performance, and delayed the neuropathological sequelae in the R6/2 transgenic mouse model of HD. Sodium butyrate also increased histone and Specificity protein-1 acetylation and protected against 3-nitropropionic acid neurotoxicity. Microarray analysis showed increased expression of
- and
-globins and MAP kinase phosphatase-1 in sodium butyrate-treated R6/2 mice, indicative of improved oxidative phosphorylation and transcriptional regulation. These findings strengthen the hypothesis that transcriptional dysfunction plays a role in the pathogenesis of HD and suggest that therapies aimed at modulating transcription may target early pathological events and provide clinical benefits to HD patients.
Key words: Huntington's disease; therapy; sodium butyrate; histones; transcription; microarray analysis; neuroprotection; R6/2 transgenic mice
Received May 24, 2003; revised August 19, 2003; accepted August 20, 2003.
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