SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice
SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice
复制标题
DOI：
10.1038/nchembio.1837
复制
发表时间：
2015-07-01
影响因子：
14.8
通讯作者：
Sivasankaran, Rajeev
中科院分区：
文献类型：
--
作者：
Palacino, James;Swalley, Susanne E.;Sivasankaran, Rajeev
脊髓性肌萎缩症（SMA）是由运动神经元生存基因（SMN 1）表达缺失引起的，是儿童死亡的最常见遗传原因。一个重复拷贝（SMN2）被无效剪接，产生一个截短的不稳定蛋白。我们在本文中描述了一种有效的口服活性小分子SMN2剪接增强剂，其在重度SMA小鼠模型中升高全长SMN蛋白并延长存活期。我们证明了作用的分子机制是通过稳定由SMN2前mRNA和U1小核核糖核酸蛋白（snRNP）复合物形成的瞬时双链RNA结构。U1 snRNP与5'剪接位点的结合亲和力以序列选择性方式增加，与组成型识别不连续。这种新的机制证明了小分子介导的序列选择性剪接调节的可行性，以及在其他剪接疾病中利用这种策略的潜力。
Spinal muscular atrophy (SMA), which results from the loss of expression of the survival of motor neuron-1 (SMN1) gene, represents the most common genetic cause of pediatric mortality. A duplicate copy (SMN2) is inefficiently spliced, producing a truncated and unstable protein. We describe herein a potent, orally active, small-molecule enhancer of SMN2 splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. We demonstrate that the molecular mechanism of action is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5' splice site is increased in a sequence-selective manner, discrete from constitutive recognition. This new mechanism demonstrates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.