In Vivo Translatome Profiling in Spinal Muscular Atrophy Reveals a Role for SMN Protein in Ribosome Biology.
In Vivo Translatome Profiling in Spinal Muscular Atrophy Reveals a Role for SMN Protein in Ribosome Biology.
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DOI：
10.1016/j.celrep.2017.10.010
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发表时间：
2017-10-24
期刊：
影响因子：
8.8
通讯作者：
Viero G
中科院分区：
文献类型：
--
作者：
Bernabò P;Tebaldi T;Groen EJN;Lane FM;Perenthaler E;Mattedi F;Newbery HJ;Zhou H;Zuccotti P;Potrich V;Shorrock HK;Muntoni F;Quattrone A;Gillingwater TH;Viero G
影响 RNA 代谢中普遍表达的蛋白质的基因改变通常会导致神经退行性疾病，越来越多的证据表明翻译缺陷可能导致疾病。脊髓性肌萎缩症（SMA）是一种由低水平SMN蛋白引起的神经肌肉疾病，其在发病机制中的作用尚不清楚。在这里，我们发现了细胞自主和 SMN 依赖的体内和体外翻译缺陷。通过并行测定 SMA 小鼠的体内转录组和翻译组，我们观察到疾病早期阶段翻译效率大幅下降。我们提供了翻译效率改变的 RNA 目录，将核糖体生物学和翻译确定为受 SMN 耗竭影响的核心过程。体内 SMA 运动神经元核糖体数量的减少进一步支持了这一点。总的来说，我们的研究结果表明核糖体生物学是运动神经元变性的一个重要但在很大程度上被忽视的因素。多核糖体分析揭示了 SMA 小鼠的翻译缺陷 翻译缺陷是 SMN 依赖性和细胞自主性 翻译效率的改变突出了核糖体生物学的缺陷 Bernabò 等人体内 SMA 中轴突核糖体的数量减少。分析了脊髓性肌萎缩症小鼠模型中的翻译，并确定了发病早期出现的翻译缺陷，这些缺陷是细胞自主的，并且伴随着患病神经中轴突核糖体数量的减少。他们的发现强调核糖体生物学是该疾病的核心标志。
Genetic alterations impacting ubiquitously expressed proteins involved in RNA metabolism often result in neurodegenerative conditions, with increasing evidence suggesting that translation defects can contribute to disease. Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, whose role in pathogenesis remains unclear. Here, we identified in vivo and in vitro translation defects that are cell autonomous and SMN dependent. By determining in parallel the in vivo transcriptome and translatome in SMA mice, we observed a robust decrease in translation efficiency arising during early stages of disease. We provide a catalogue of RNAs with altered translation efficiency, identifying ribosome biology and translation as central processes affected by SMN depletion. This was further supported by a decrease in the number of ribosomes in SMA motor neurons in vivo. Overall, our findings suggest ribosome biology as an important, yet largely overlooked, factor in motor neuron degeneration. Polysomal profiling reveals translation defects in SMA mice Translation defects are SMN dependent and cell autonomous Translation efficiency alterations highlight defects in ribosome biology The number of axonal ribosomes is decreased in SMA in vivo Bernabò et al. analyzed translation in a mouse model of spinal muscular atrophy and identified translation defects that arise early in pathogenesis, are cell autonomous, and are accompanied by a low number of axonal ribosomes in diseased nerves. Their findings highlight ribosome biology as a central hallmark of the disease.
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DOI：
10.1261/rna.053561.115
发表时间：
2016-06
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Carlevaro-Fita J;Rahim A;Guigó R;Vardy LA;Johnson R
通讯作者：
Johnson R
影响因子：
3.5
作者：
Coyne, Alyssa N.;Yamada, Shizuka B.;Zarnescu, Daniela C.
通讯作者：
Zarnescu, Daniela C.
影响因子：
4
作者：
Gabanella, Francesca;Pisani, Cinzia;Di Certo, Maria Grazia
通讯作者：
Di Certo, Maria Grazia
影响因子：
4.5
作者：
Bäumer D;Lee S;Nicholson G;Davies JL;Parkinson NJ;Murray LM;Gillingwater TH;Ansorge O;Davies KE;Talbot K
通讯作者：
Talbot K
影响因子：
64.8
作者：
Dragon, F;Gallagher, JEG;Baserga, SJ
通讯作者：
Baserga, SJ