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Pre-natal manifestation of systemic developmental abnormalities in spinal muscular atrophy.
Human Molecular Genetics ( IF 3.5 ) Pub Date : 2020-07-09 , DOI: 10.1093/hmg/ddaa146
Anna A L Motyl 1, 2 , Kiterie M E Faller 3 , Ewout J N Groen 4 , Rachel A Kline 2, 5 , Samantha L Eaton 2, 5 , Leire M Ledahawsky 1, 2 , Helena Chaytow 1, 2 , Douglas J Lamont 6 , Thomas M Wishart 2, 5 , Yu-Ting Huang 1, 2 , Thomas H Gillingwater 1, 2
Affiliation  

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in survival motor neuron 1 (SMN1). SMN-restoring therapies have recently emerged; however, pre-clinical and clinical studies revealed a limited therapeutic time-window and systemic aspects of the disease. This raises a fundamental question of whether SMA has pre-symptomatic, developmental components to disease pathogenesis. We have addressed this by combining micro-computed tomography (μCT) and comparative proteomics to examine systemic pre-symptomatic changes in a prenatal mouse model of SMA. Quantitative μCT analyses revealed that SMA embryos were significantly smaller than littermate controls, indicative of general developmental delay. More specifically, cardiac ventricles were smaller in SMA hearts, whilst liver and brain remained unaffected. In order to explore the molecular consequences of SMN depletion during development, we generated comprehensive, high-resolution, proteomic profiles of neuronal and non-neuronal organs in SMA mouse embryos. Significant molecular perturbations were observed in all organs examined, highlighting tissue-specific prenatal molecular phenotypes in SMA. Together, our data demonstrate considerable systemic changes at an early, pre-symptomatic stage in SMA mice, revealing a significant developmental component to SMA pathogenesis.

中文翻译:

脊髓性肌萎缩症全身发育异常的产前表现。

脊髓性肌萎缩症 (SMA) 是一种由运动神经元存活 1 ( SMN1)突变引起的神经肌肉疾病)。最近出现了 SMN 恢复疗法;然而,临床前和临床研究揭示了该疾病的有限治疗时间窗和全身性方面。这提出了一个基本问题,即 SMA 是否具有疾病发病机制的症状前、发育成分。我们通过结合微计算机断层扫描 (μCT) 和比较蛋白质组学来检查产前 SMA 小鼠模型的全身症状前变化,从而解决了这个问题。定量 μCT 分析显示 SMA 胚胎明显小于同窝对照,表明普遍发育迟缓。更具体地说,SMA 心脏中的心室较小,而肝脏和大脑未受影响。为了探索发育过程中 SMN 耗竭的分子后果,我们生成了全面、高分辨率、SMA 小鼠胚胎中神经元和非神经元器官的蛋白质组学特征。在所有检查的器官中都观察到显着的分子扰动,突出了 SMA 中组织特异性的产前分子表型。总之,我们的数据表明 SMA 小鼠在早期、症状前阶段发生了相当大的系统性变化,揭示了 SMA 发病机制的重要发育组成部分。
更新日期:2020-07-09
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