Unitat de Senyalització Neuronal, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida-IRBLLEIDA, Montserrat Roig, 2. 25008-Lleida, Spain.
Neurobiol Dis. 2011 Jun;42(3):415-26. doi: 10.1016/j.nbd.2011.02.003. Epub 2011 Feb 16.
Spinal muscular atrophy (SMA) is a motoneuron disorder characterized by deletions or specific mutations in the Survival Motor Neuron gene (SMN). SMN is ubiquitously expressed and has a general role in the assembly of small nuclear ribonucleoprotein (snRNP) and pre-mRNA splicing requirements. However, in motoneuron axons SMN deficiency results in inappropriate levels of certain transcripts in the distal axon, suggesting that the specific susceptibility of motoneurons to SMN deficiency is related to a specialized function in these cells. Although mouse models of SMA have been generated and are useful for in vivo and in vitro studies, the limited number of isolated MNs that could be obtained from them makes it difficult to perform biochemical, genetic and pharmacological approaches. We describe here an in vitro model of isolated embryonic mouse motoneurons in which the cellular levels of endogenous SMN are reduced. These cells show neurite degeneration and cell death after several days of SMN knockdown. We found that the over-expression of the anti-apoptotic protein Bcl-x(L) into motoneurons rescues these cells from the phenotypic changes observed. This result demonstrates that Bcl-x(L) signaling could be a possible pharmacological target of SMA therapeutics.
脊髓性肌萎缩症（SMA）是一种运动神经元疾病，其特征是生存运动神经元基因（SMN）缺失或特定突变。SMN 广泛表达，在小核核糖核蛋白（snRNP）的组装和前体 mRNA 剪接要求中具有一般作用。然而，在运动神经元轴突中，SMN 缺乏导致远端轴突中某些转录物的水平不当，这表明运动神经元对 SMN 缺乏的特殊易感性与这些细胞中的特殊功能有关。尽管已经产生了 SMA 的小鼠模型，并且可用于体内和体外研究，但从它们中获得的分离的 MN 数量有限，使得难以进行生化、遗传和药理学方法。我们在这里描述了一种分离的胚胎小鼠运动神经元的体外模型，其中内源性 SMN 的细胞水平降低。在 SMN 敲低数天后，这些细胞显示出神经突退化和细胞死亡。我们发现，将抗凋亡蛋白 Bcl-x(L)过表达到运动神经元中，可以挽救这些细胞免受观察到的表型变化。这一结果表明，Bcl-x(L)信号可能是 SMA 治疗的潜在药理学靶点。
