Gavrilina Tatiana O, McGovern Vicki L, Workman Eileen, Crawford Thomas O, Gogliotti Rocky G, DiDonato Christine J, Monani Umrao R, Morris Glenn E, Burghes Arthur H M
Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
Hum Mol Genet. 2008 Apr 15;17(8):1063-75. doi: 10.1093/hmg/ddm379. Epub 2008 Jan 4.
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.
脊髓性肌萎缩症（SMA）是由生存运动神经元基因（SMN1）缺失和SMN2基因保留引起的。SMN2的拷贝数影响所产生的SMN蛋白的量以及SMA表型的严重程度。虽然小鼠Smn基因缺失会导致胚胎致死，但两个拷贝的SMN2可防止这种胚胎致死性，从而产生一只患有严重SMA的小鼠，该小鼠在出生后5天死亡。在此我们表明，在朊病毒启动子（PrP）控制下全长SMN的表达可挽救严重SMA小鼠。PrP在胚胎第15天导致神经元中高水平的SMN。具有两个拷贝的SMN2且缺失小鼠Smn的PrP-SMN纯合小鼠平均存活210天，并且这些小鼠的腰运动神经元神经根计数正常。使用人骨骼肌肌动蛋白（HSA）启动子仅在骨骼肌中表达SMN并未改善SMA表型或延长生存期。一个显示SMN在神经中表达的HSA系确实影响了SMA表型，小鼠平均存活160天。因此，我们得出结论，在神经元中全长SMN的表达可以纠正小鼠严重的SMA表型。此外，神经元中SMN的少量增加对SMA小鼠的存活有重大影响，而仅在成熟骨骼肌中高SMN水平则没有影响。
