Valproic acid increases SMN2 expression and modulates SF2/ASF and hnRNPA1 expression in SMA fibroblast cell lines
Valproic acid increases SMN2 expression and modulates SF2/ASF and hnRNPA1 expression in SMA fibroblast cell lines
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DOI：
10.1016/j.braindev.2011.04.010
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发表时间：
2012-03-01
影响因子：
1.7
通讯作者：
Nishio, Hisahide
中科院分区：
文献类型：
--
作者：
Harahap, Indra Sari Kusuma;Saito, Toshio;Nishio, Hisahide
脊髓性肌萎缩症（SMA）是一种常见的常染色体隐性遗传性神经肌肉疾病，是由运动神经元存活基因SAM 1丢失引起的。SMA治疗策略集中于从几乎相同的基因SMN 2产生SMN蛋白。丙戊酸（VPA）是一种组蛋白脱乙酰酶抑制剂，可通过激活SMN 2转录或SMN 2外显子7的剪接校正来增加某些SMA细胞或SMA患者的SMN水平。需要何种浓度的VPA以及通过何种机制诱导SMN 2产生SMN仍有待澄清。我们观察到，在日本SMA患者的两种成纤维细胞系中，超过1 mM的VPA在转录物和蛋白质水平上均增加了SMN 2的表达。VPA不仅增加了细胞系中全长（FL）转录水平，还增加了外显子7排除（Delta 7）转录水平，但未改变FL/Delta 7的比值，表明SMN 2转录主要被激活。我们还发现，VPA调节剪接因子的表达：VPA增加剪接因子2/选择性剪接因子（SF 2/ASF）的表达，并降低异质核核糖核蛋白A1（hnRNPA 1）的表达。总之，在我们的SMA成纤维细胞系中，超过1 mM的VPA可激活SMN 2转录并调节剪接因子的表达。(C)2011年日本儿童神经病学学会。Elsevier B. V.出版，保留所有权利。
Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is caused by loss of the survival motor neuron gene, SAM1. SMA treatment strategies have focused on production of the SMN protein from the almost identical gene, SMN2. Valproic acid (VPA) is a histone deacetylase inhibitor that can increase SMN levels in some SMA cells or SMA patients through activation of SMN2 transcription or splicing correction of SMN2 exon 7. It remains to be clarified what concentration of VPA is required and by what mechanisms the SMN production from SMN2 is elicited. We observed that in two fibroblast cell lines from Japanese SMA patients, more than 1 mM of VPA increased SMN2 expression at both the transcript and protein levels. VPA increased not only full-length (FL) transcript level but also exon 7-excluding (Delta 7) transcript level in the cell lines and did not change the ratio of FL/Delta 7, suggesting that SMN2 transcription was mainly activated. We also found that VPA modulated splicing factor expression: VPA increased the expression of splicing factor 2/alternative splicing factor (SF2/ASF) and decreased the expression of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). In conclusion, more than 1 mM of VPA activated SMN2 transcription and modulated the expression of splicing factors in our SMA fibroblast cell lines. (C) 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.