Bowerman Mélissa, Shafey Dina, Kothary Rashmi
Ottawa Health Research Institute, Ottawa, ON, Canada.
J Mol Neurosci. 2007;32(2):120-31. doi: 10.1007/s12031-007-0024-5.
Spinal muscular atrophy (SMA) is the most common genetic disease resulting in infant mortality due to severe loss of alpha-motor neurons. SMA is caused by mutations or deletions of the ubiquitously expressed survival motor neuron (SMN) gene. However, why alpha-motor neurons of SMA patients are specifically affected is not clear. We demonstrate here that Smn knockdown in PC12 cells alters the expression pattern of profilin II, resulting in an increase in the neuronal-specific profilin IIa isoform. Moreover, the depletion of Smn, a known interacting partner of profilin IIa, further contributes to the increased profilin IIa availability. Altogether, this leads to an increased formation of ROCK/profilin IIa complex and an inappropriate activation of the RhoA/ROCK pathway, resulting in altered cytoskeletal integrity and a subsequent defect in neuritogenesis. This study represents the first description of a mechanism underlying SMA pathogenesis and highlights new targets for therapeutic intervention for this devastating disorder.
脊髓性肌萎缩症（SMA）是导致婴儿死亡的最常见的遗传性疾病，原因是α运动神经元严重缺失。SMA由普遍表达的生存运动神经元（SMN）基因突变或缺失引起。然而，SMA患者的α运动神经元为何受到特异性影响尚不清楚。我们在此证明，PC12细胞中Smn基因敲低会改变丝切蛋白II的表达模式，导致神经元特异性丝切蛋白IIa亚型增加。此外，作为丝切蛋白IIa已知相互作用伴侣的Smn的缺失，进一步导致丝切蛋白IIa可用性增加。总之，这导致ROCK/丝切蛋白IIa复合物形成增加以及RhoA/ROCK通路的不适当激活，从而导致细胞骨架完整性改变以及随后的神经突形成缺陷。本研究首次描述了SMA发病机制的潜在机制，并突出了针对这种毁灭性疾病的治疗干预新靶点。
