Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect
Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect
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DOI：
10.1093/hmg/ddm379
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发表时间：
2008-04-15
影响因子：
3.5
通讯作者：
Burghes, Arthur H. M.
中科院分区：
文献类型：
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作者：
Gavrilina, Tatiana O.;McGovern, Vicki L.;Burghes, Arthur H. M.
脊髓性肌萎缩症 (SMA) 是由运动神经元存活基因 (SMN1) 缺失和 SMN2 基因保留引起的。 SMN2 的拷贝数影响 SMN 蛋白的产生量和 SMA 表型的严重程度。虽然小鼠 Smn 的缺失会导致胚胎致死，但 SMN2 的两个拷贝可以防止这种胚胎致死，从而导致患有严重 SMA 的小鼠在出生 5 天后死亡。在这里，我们展示了在朊病毒启动子 (PrP) 下表达全长 SMN 可以拯救严重的 SMA 小鼠。 PrP 导致胚胎第 15 天神经元中的 SMN 水平较高。具有两个 SMN2 拷贝且缺乏小鼠 Smn 的 PrP-SMN 纯合子小鼠平均存活 210 天，并且这些小鼠的腰部运动神经元根计数正常。使用人骨骼肌动蛋白 (HSA) 启动子仅在骨骼肌中表达 SMN 不会导致 SMA 表型的改善或生存的延长。一条显示 SMN 神经表达的 HSA 系确实影响平均存活 160 天的小鼠的 SMA 表型。因此，我们得出结论，神经元中全长 SMN 的表达可以纠正小鼠严重的 SMA 表型。此外，神经元中 SMN 的小幅增加对 SMA 小鼠的生存具有重大影响，而成熟骨骼肌中 SMN 的高水平单独没有影响。
Spinal muscular atrophy (SMA) is caused by loss of the survival motor neuron gene (SMN1) and retention of the SMN2 gene. The copy number of SMN2 affects the amount of SMN protein produced and the severity of the SMA phenotype. While loss of mouse Smn is embryonic lethal, two copies of SMN2 prevents this embryonic lethality resulting in a mouse with severe SMA that dies 5 days after birth. Here we show that expression of full-length SMN under the prion promoter (PrP) rescues severe SMA mice. The PrP results in high levels of SMN in neurons at embryonic day 15. Mice homozygous for PrP-SMN with two copies of SMN2 and lacking mouse Smn survive for an average of 210 days and lumbar motor neuron root counts in these mice were normal. Expression of SMN solely in skeletal muscle using the human skeletal actin (HSA) promoter resulted in no improvement of the SMA phenotype or extension of survival. One HSA line displaying nerve expression of SMN did affect the SMA phenotype with mice living for an average of 160 days. Thus, we conclude that expression of full-length SMN in neurons can correct the severe SMA phenotype in mice. Furthermore, a small increase of SMN in neurons has a substantial impact on survival of SMA mice while high SMN levels in mature skeletal muscle alone has no impact.