Journal
JOURNAL OF NEUROSCIENCE
Volume 24, Issue 46, Pages 10335-10342Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2599-04.2004
Keywords
mithramycin; Huntington's disease; HD; Huntingtin; Htt; histone methylation; neuroprotection; transcription
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Funding
- NCCIH NIH HHS [AT00613, U01 AT000613, R01 AT000613] Funding Source: Medline
- NINDS NIH HHS [F32 NS046239, U01 NS045806, R01 NS040591-03, NS045806, R01 NS040591, NS35255, P01 NS045242, NS40591, NS045242, NS46239] Funding Source: Medline
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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.
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