Impaired Local Translation of β-actin mRNA in Ighmbp2-Deficient Motoneurons: Implications for Spinal Muscular Atrophy with respiratory Distress (SMARD1)
Impaired Local Translation of β-actin mRNA in Ighmbp2-Deficient Motoneurons: Implications for Spinal Muscular Atrophy with respiratory Distress (SMARD1)
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Ighmbp2 缺陷运动神经元中 β 肌动蛋白 mRNA 的局部翻译受损：对脊髓性肌萎缩伴呼吸窘迫的影响 (SMARD1)
DOI：
10.1016/j.neuroscience.2018.06.019
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发表时间：
2018
期刊：
影响因子：
3.3
通讯作者：
Jablonka S
中科院分区：
文献类型：
--
作者：
Surrey V;Zöller C;Lork AA;Moradi M;Balk S;Dombert B;Saal-Bauernschubert L;Briese M;Appenzeller S;Fischer U;Jablonka S
脊髓性肌萎缩症合并呼吸窘迫1型(SMARD1)是一种病因不明的儿童致命性运动神经元疾病。这种疾病是由编码超级家族1(SF1)型RNA/DNA解旋酶的IGHMBP基因突变引起的。IGHMBP2是一种胞质蛋白，与核糖体和多聚体结合，提示在mRNA代谢中发挥作用。在这里，我们对分离的免疫球蛋白μ结合蛋白2(IghMbp2)缺乏的运动神经元进行了形态和功能分析，以解决SMARD1表型是否是蛋白质生物合成失调的结果的问题。Ighmbp2基因缺陷的运动神经元仅表现出轻微的形态异常，如轴突分支的轻微增加。与相当轻微的表型异常一致，Ighmbp2缺陷运动神经元的RNA测序显示，与对照组相比，只有轻微的转录组变化。同样，我们没有使用脉冲SILAC(细胞培养中氨基酸稳定同位素标记)、FUNCAT(荧光非典型氨基酸标记)和Sunset(翻译表面传感)方法检测到蛋白质合成的任何全球变化。然而，我们观察到Ighmbp2缺陷运动神经元生长锥体β-肌动蛋白水平降低，并伴随着已知的β-肌动蛋白mRNA相互作用蛋白IMP1ZBP1水平的降低。光漂白后荧光恢复(FRAP)研究显示，生长锥体中EGFP-myr-β-肌动蛋白3‘UTRmRNA的翻译下调。β-肌动蛋白基因的局部翻译调控依赖于3‘端非编码区，而不依赖于IghMBp2与β-肌动蛋白基因的直接结合。综上所述，我们的数据表明，Ighmbp2缺乏导致局部但轻微的蛋白质生物合成中断，这可能是SMARD1中看到的运动神经元缺陷的部分原因。
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a fatal motoneuron disorder in children with unknown etiology. The disease is caused by mutations in theIGHMBP2gene, encoding a Super Family 1 (SF1)-type RNA/DNA helicase. IGHMBP2 is a cytosolic protein that binds to ribosomes and polysomes, suggesting a role in mRNA metabolism. Here we performed morphological and functional analyses of isolated immunoglobulin μ-binding protein 2 (Ighmbp2)-deficient motoneurons to address the question whether the SMARD1 phenotype results from de-regulation of protein biosynthesis. Ighmbp2-deficient motoneurons exhibited only moderate morphological aberrations such as a slight increase of axonal branches. Consistent with the rather mild phenotypic aberrations, RNA sequencing of Ighmbp2-deficient motoneurons revealed only minor transcriptome alterations compared to controls. Likewise, we did not detect any global changes in protein synthesis using pulsed SILAC (Stable Isotope Labeling by Amino acids in Cell culture), FUNCAT (FlUorescent Non-Canonical Amino acid Tagging) and SUnSET (SUrface SEnsing of Translation) approaches. However, we observed reduced β-actin protein levels at the growth cone of Ighmbp2-deficient motoneurons which was accompanied by reduced level of IMP1/ZBP1, a known interactor of β-actin mRNA. Fluorescence Recovery after Photobleaching (FRAP) studies revealed translational down-regulation of an eGFP-myr-β-actin 3′UTR mRNA in growth cones. Local translational regulation of β-actin mRNA was dependent on the 3′ UTR but independent of direct Ighmbp2-binding to β-actin mRNA. Taken together, our data indicate that Ighmbp2 deficiency results in local but modest disruption of protein biosynthesis which might partially contribute to the motoneuron defects seen in SMARD1.
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