A SMNDelta7 read-through product confers functionality to the SMNDelta7 protein.
A SMNDelta7 read-through product confers functionality to the SMNDelta7 protein.
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SMNDelta7 通读产品赋予 SMNDelta7 蛋白功能。
DOI：
10.1016/j.neulet.2008.06.059
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发表时间：
2008
影响因子：
2.5
通讯作者：
Lorson,ChristianL
中科院分区：
文献类型：
--
作者：
Mattis,VirginiaB;Bowerman,Melissa;Kothary,Rashmi;Lorson,ChristianL
脊髓性肌萎缩症(SMA)每6000名新生儿中就有1人受到影响，是导致婴儿死亡的主要遗传原因。SMA是一种由存活运动神经元-1(SMN1)突变或缺失引起的隐性疾病。SMN2是一个几乎相同的复制基因，有可能编码与SMN1相同的蛋白质，并在所有SMA患者中保留。大多数SMN2源的转录本是选择性剪接的，因此编码一个缺失外显子7的截短异构体(SMNΔ7)，这是一种缺陷蛋白质，因为它不稳定，自结合能力降低，无法有效地发挥SMN细胞活动的功能。然而，我们已经证明了SMN C末端的功能是非特异性的，因为异源序列可以补偿外显子7序列。在SMN诱导的高通量筛选中鉴定的几类化合物已被提出通过通读机制发挥作用；然而，尚未对SMNΔ7通读产物进行功能分析。在这份报告中，对SMNΔ7通读产物进行了表征，并与SMNΔ7蛋白进行了比较。在一系列体外和基于细胞的检测中，SMNRNP 7通读产物被证明增加了蛋白质的稳定性，促进了SMN缺陷神经元的突起生长，并显著增加了SMN依赖的Δ在成纤维细胞中的组装。综上所述，这些结果表明，SMNΔ7通读产物比SMNΔ7蛋白更具活性，并提示特异性诱导SMNΔ7通读的SMA疗法可能为药物发现提供一个替代平台。
Spinal muscular atrophy (SMA) affects about 1 in every 6000 children born and is the leading genetic cause of infant death. SMA is a recessive disorder caused by the mutation or deletion of Survival Motor Neuron-1 (SMN1). SMN2, a nearly identical copy gene, has the potential to encode the same protein as SMN1 and is retained in all SMA patients. The majority of SMN2-derived transcripts are alternatively spliced and therefore encode a truncated isoform lacking exon 7 (SMNΔ7), which is a defective protein because it is unstable, has a reduced ability to self-associate and is unable to efficiently function in SMN cellular activities. However, we have shown that the SMN C-terminus functions non-specifically, since heterologous sequences can compensate for the exon 7 sequence. Several classes of compounds identified in SMN-inducing high throughput screens have been proposed to function through a read-through mechanism; however, a functional analysis of the SMNΔ7 read-through product has not been performed. In this report, the SMNΔ7 read-through product is characterized and compared to the SMNΔ7 protein. In a series of in vitro and cell based assays, SMNΔ7 read-through product is shown to increase protein stability, promote neurite outgrowths in SMN deficient neurons, and significantly elevate SMN-dependent UsnRNP assembly in extracts from SMA patient fibroblasts. Collectively, these results demonstrate that SMNΔ7 read-through product is more active than the SMNΔ7 protein and suggest that SMA therapeutics that specifically induce SMNΔ7 read-through may provide an alternative platform for drug discovery.