Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy
Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy
复制标题
DOI：
10.1172/jci29562
复制
发表时间：
2007-03-01
影响因子：
15.9
通讯作者：
Sumner, Charlotte J.
中科院分区：
文献类型：
--
作者：
Avila, Amy M.;Burnett, Barrington G.;Sumner, Charlotte J.
遗传性运动神经元病脊髓性肌萎缩症 (SMA) 是由端粒存活运动神经元 1 (SMN1) 基因突变并保留着丝粒 SMN2 基因引起的。我们试图确定强效且特异的异羟肟酸类组蛋白脱乙酰酶 (HDAC) 抑制剂是否能在体内激活 SMN2 基因表达，并在疾病发作后使用时调节 SMA 疾病表型。在非转基因和 SMA 模型小鼠中，单次腹腔注射 10 mg/kg 曲古抑菌素 A (TSA) 可导致乙酰化 H3 和 H4 组蛋白水平增加，并适度增加 SMN 基因表达。每日重复剂量的 TSA 导致神经组织和肌肉中 SMN2 衍生转录物和 SMN 蛋白水平增加，这与小核核糖核蛋白 (snRNP) 组装的改善有关。当从 PS 开始每天给予 TSA 时，在体重减轻和运动缺陷出现后，生存率提高，体重减轻减弱，运动行为增强。病理分析显示肌纤维尺寸和数量增加，前角细胞尺寸增加。这些结果表明，异羟肟酸类 HDAC 抑制剂在体内激活 SMN2 基因表达，并且在疾病发作后施用时对 SMA 疾病表型具有改善作用。
The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by mutation of the telomeric survival motor neuron 1 (SMN1) gene with retention of the centromeric SMN2 gene. We sought to establish whether the potent and specific hydroxamic acid class of histone deacetylase (HDAC) inhibitors activates SMN2 gene expression in vivo and modulates the SMA disease phenotype when delivered after disease onset. Single intraperitoneal doses of 10 mg/kg trichostatin A (TSA) in nontransgenic and SMA model mice resulted in increased levels of acetylated H3 and H4 histones and modest increases in SMN gene expression. Repeated daily doses of TSA caused increases in both SMN2-derived transcript and SMN protein levels in neural tissues and muscle, which were associated with an improvement in small nuclear ribonucleoprotein (snRNP) assembly. When TSA was delivered daily beginning on PS, after the onset of weight loss and motor deficit, there was improved survival, attenuated weight loss, and enhanced motor behavior. Pathological analysis showed increased myofiber size and number and increased anterior horn cell size. These results indicate that the hydroxamic acid class of HDAC inhibitors activates SMN2 gene expression in vivo and has an ameliorating effect on the SMA disease phenotype when administered after disease onset.