Antoine Marie, Patrick Kristin L, Soret Johann, Duc Pauline, Rage Florence, Cacciottolo Rebecca, Nissen Kelly E, Cauchi Ruben J, Krogan Nevan J, Guthrie Christine, Gachet Yannick, Bordonné Rémy
Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France.
University of California, San Francisco, CA 94143, USA.
iScience. 2020 Jan 24;23(1):100809. doi: 10.1016/j.isci.2019.100809. Epub 2019 Dec 28.
Spinal muscular atrophy (SMA) is a devastating motor neuron disorder caused by mutations in the survival motor neuron (SMN) gene. It remains unclear how SMN deficiency leads to the loss of motor neurons. By screening Schizosaccharomyces pombe, we found that the growth defect of an SMN mutant can be alleviated by deletion of the actin-capping protein subunit gene acp1. We show that SMN mutated cells have splicing defects in the profilin gene, which thus directly hinder actin cytoskeleton homeostasis including endocytosis and cytokinesis. We conclude that deletion of acp1 in an SMN mutant background compensates for actin cytoskeleton alterations by restoring redistribution of actin monomers between different types of cellular actin networks. Our data reveal a direct correlation between an impaired function of SMN in snRNP assembly and defects in actin dynamics. They also point to important common features in the pathogenic mechanism of SMA and ALS.
脊髓性肌萎缩症（SMA）是一种由存活运动神经元（SMN）基因突变引起的毁灭性运动神经元疾病。目前尚不清楚SMN缺乏如何导致运动神经元丧失。通过对粟酒裂殖酵母进行筛选，我们发现SMN突变体的生长缺陷可通过缺失肌动蛋白封端蛋白亚基基因acp1得到缓解。我们表明，SMN突变细胞在丝切蛋白基因中存在剪接缺陷，从而直接阻碍包括内吞作用和胞质分裂在内的肌动蛋白细胞骨架稳态。我们得出结论，在SMN突变背景下缺失acp1可通过恢复肌动蛋白单体在不同类型细胞肌动蛋白网络之间的重新分布来补偿肌动蛋白细胞骨架改变。我们的数据揭示了SMN在小核核糖核蛋白组装中的功能受损与肌动蛋白动力学缺陷之间的直接关联。它们还指出了SMA和肌萎缩侧索硬化症（ALS）致病机制中的重要共同特征。
