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The Journal of Neuroscience, November 17, 2004, 24(46):10335-10342; doi:10.1523/JNEUROSCI.2599-04.2004
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Neurobiology of Disease
Chemotherapy for the Brain: The Antitumor Antibiotic Mithramycin Prolongs Survival in a Mouse Model of Huntington's Disease
Robert J. Ferrante,1 Hoon Ryu,1 James K. Kubilus,1 Santosh D'Mello,2 Katharine L. Sugars,3 Junghee Lee,1 Peiyuan Lu,4 Karen Smith,1 Susan Browne,7 M. Flint Beal,7 Bruce S. Kristal,7,8 Irina G. Stavrovskaya,7,8 Sandra Hewett,9 David C. Rubinsztein,3 Brett Langley,4 andRajiv R. Ratan4,5,6,7,8 1Geriatric Research and Education and Clinical Center, Veterans Administration Medical Center, Bedford, Department of Neurology, Pathology, and Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, 2Department of Molecular and Cellular Biology, University of Texas at Dallas, Richardson, Texas 75083, 3Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, CB2 2XY United Kingdom, 4Department of Neurology, 5Program in Neuroscience, and 6Center for Neurodegeneration and Repair, Harvard Medical School and The Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, 7Department of Neurology and Neuroscience, Weil Medical College of Cornell University, New York, New York 10021, 8Burke Medical Research Institute, White Plains, New York 10605, and 9University of Connecticut School of Medicine, Farmington, Connecticut 06030
Huntington's disease (HD) is a fully penetrant autosomal-dominant inherited neurological disorder caused by expanded CAG repeats in the Huntingtin gene. Transcriptional dysfunction, excitotoxicity, and oxidative stress have all been proposed to play important roles in the pathogenesis of HD. This study was designed to explore the therapeutic potential of mithramycin, a clinically approved guanosine-cytosine-rich DNA binding antitumor antibiotic. Pharmacological treatment of a transgenic mouse model of HD (R6/2) with mithramycin extended survival by 29.1%, greater than any single agent reported to date. Increased survival was accompanied by improved motor performance and markedly delayed neuropathological sequelae. To identify the functional mechanism for the salubrious effects of mithramycin, we examined transcriptional dysfunction in R6/2 mice. Consistent with transcriptional repression playing a role in the pathogenesis of HD, we found increased methylation of lysine 9 in histone H3, a well established mechanism of gene silencing. Mithramycin treatment prevented the increase in H3 methylation observed in R6/2 mice, suggesting that the enhanced survival and neuroprotection might be attributable to the alleviation of repressed gene expression vital to neuronal function and survival. Because it is Food and Drug Administration-approved, mithramycin is a promising drug for the treatment of HD.
Key words: mithramycin; Huntington's disease; HD; Huntingtin; Htt; histone methylation; neuroprotection; transcription
Received June 30, 2004; revised October 7, 2004; accepted October 8, 2004.
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