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
Geriatric Research and Education and Clinical Center, Veterans Administration Medical Center, Bedford, MA, USA.
J Neurosci. 2004 Nov 17;24(46):10335-42. doi: 10.1523/JNEUROSCI.2599-04.2004.
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.
亨廷顿舞蹈症（HD）是一种完全显性的常染色体显性遗传性神经疾病，由亨廷顿基因中CAG重复序列扩增引起。转录功能障碍、兴奋性毒性和氧化应激均被认为在HD的发病机制中起重要作用。本研究旨在探索光辉霉素的治疗潜力，光辉霉素是一种临床批准的富含鸟嘌呤 - 胞嘧啶的DNA结合抗肿瘤抗生素。用光辉霉素对HD转基因小鼠模型（R6/2）进行药物治疗可使生存期延长29.1%，这比迄今为止报道的任何单一药物效果都要好。生存期的延长伴随着运动能力的改善和神经病理后遗症的显著延迟。为了确定光辉霉素有益作用的功能机制，我们检测了R6/2小鼠的转录功能障碍。鉴于转录抑制在HD发病机制中起作用，我们发现组蛋白H3赖氨酸9位点甲基化增加，这是一种成熟的基因沉默机制。光辉霉素治疗可防止R6/2小鼠中观察到的H3甲基化增加，这表明生存期延长和神经保护作用可能归因于对神经元功能和生存至关重要的基因表达抑制的减轻。由于光辉霉素已获得美国食品药品监督管理局批准，它是一种有前景的HD治疗药物。
