Chemotherapy for the Brain: The Antitumor Antibiotic Mithramycin Prolongs Survival in a Mouse Model of Huntington's Disease

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. Th...

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Bibliographic Details
Published in:The Journal of neuroscience 2004-11, Vol.24 (46), p.10335-10342
Main Authors: Ferrante, Robert J, Ryu, Hoon, Kubilus, James K, D'Mello, Santosh, Sugars, Katharine L, Lee, Junghee, Lu, Peiyuan, Smith, Karen, Browne, Susan, Beal, M. Flint, Kristal, Bruce S, Stavrovskaya, Irina G, Hewett, Sandra, Rubinsztein, David C, Langley, Brett, Ratan, Rajiv R
Format: Article
Language:English
Subjects:
Animals
Antibiotics, Antineoplastic - pharmacology
Antibiotics, Antineoplastic - therapeutic use
Brain - pathology
Cells, Cultured
Gene Silencing
Humans
Huntingtin Protein
Huntington Disease - drug therapy
Huntington Disease - mortality
Huntington Disease - pathology
In Vitro Techniques
Lysine - metabolism
Male
Methylation
Mice
Mice, Transgenic
Mitochondria, Liver - drug effects
Mitochondria, Liver - metabolism
Motor Activity - drug effects
N-Methylaspartate - pharmacology
Nerve Tissue Proteins - biosynthesis
Nerve Tissue Proteins - genetics
Neurobiology of Disease
Neurons - cytology
Neurons - drug effects
Nuclear Proteins - biosynthesis
Nuclear Proteins - genetics
Plicamycin - pharmacology
Plicamycin - therapeutic use
Rats
Rats, Inbred BN
Rats, Inbred F344
Receptors, Glutamate - drug effects
Receptors, Glutamate - physiology
Transcription, Genetic
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Summary: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.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.2599-04.2004