Mitochondrial dysfunction reveals the role of mRNA poly(A) tail regulation in oculopharyngeal muscular dystrophy pathogenesis.
Mitochondrial dysfunction reveals the role of mRNA poly(A) tail regulation in oculopharyngeal muscular dystrophy pathogenesis.
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DOI：
10.1371/journal.pgen.1005092
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发表时间：
2015-03
期刊：
影响因子：
4.5
通讯作者：
Simonelig M
中科院分区：
文献类型：
--
作者：
Chartier A;Klein P;Pierson S;Barbezier N;Gidaro T;Casas F;Carberry S;Dowling P;Maynadier L;Bellec M;Oloko M;Jardel C;Moritz B;Dickson G;Mouly V;Ohlendieck K;Butler-Browne G;Trollet C;Simonelig M
眼咽肌营养不良症（OPMD）是一种以特定肌肉进行性退行性变为特征的晚发性疾病，由聚(a)结合蛋白核1 （PABPN1）中聚丙氨酸束的延伸引起。虽然PABPN1在核聚腺苷化和调控选择性聚(A)位点选择中的作用已经确定，但OPMD背后的分子机制仍未确定。在这里，我们使用果蝇和小鼠模型表明，OPMD的发病机制取决于特定mrna的受影响的聚(A)尾长度。我们发现了一组编码线粒体蛋白的mrna，这些mrna在OPMD进展的早期阶段就开始下调。这些mrna的下调与其缩短的聚(A)尾有关，当deadenylation基因减少时，其水平的部分恢复可以改善肌肉功能。利用果蝇OPMD模型对编码RNA结合蛋白的候选基因进行遗传分析，揭示了其中一些基因的潜在作用。我们重点研究了死蛋白化调节因子Smaug，发现它在成人肌肉中表达，并特异性地与下调的mrna结合。此外，在表达丙氨酸扩增型PABPN1的肌肉中，裂解和多腺苷化反应的第一步mRNA裂解也受到影响。我们认为，在核分裂/聚腺苷化过程中受损的卵裂是OPMD的早期缺陷。这种缺陷伴随着特异性mrna的活性死蛋白化，包括Smaug和CCR4-NOT死蛋白化复合物，导致它们的不稳定和线粒体功能障碍。这些结果拓宽了我们对mRNA调控在病理中的作用的理解，并可能有助于理解涉及线粒体功能障碍的神经退行性疾病的分子机制。眼咽肌营养不良是一种遗传性疾病，其特征是特定肌肉的进行性变性，导致上睑下垂（眼睑下垂）、吞咽困难（吞咽困难）和近端肢体无力。这种疾病是由一种称为聚(a)结合蛋白核1的核蛋白突变引起的，该蛋白参与信使rna （mrna）的聚腺苷化和聚(a)位点选择。为了解决与疾病有关的分子机制，我们使用了两种动物模型（果蝇和小鼠）来概括这种疾病的特征。我们发现眼咽肌营养不良的发病机制取决于特定mrna的聚(A)尾长调节缺陷。由于多聚(A)尾在mRNA的稳定性中起着至关重要的作用，这些缺陷导致这些mRNA的加速衰变。受影响的mrna编码线粒体蛋白，患病肌肉的线粒体活性受损。这些发现对于开发眼咽肌营养不良的潜在治疗方法具有重要意义，并且可能与破译涉及线粒体功能障碍的其他疾病的分子机制有关。
Oculopharyngeal muscular dystrophy (OPMD), a late-onset disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using Drosophila and mouse models, that OPMD pathogenesis depends on affected poly(A) tail lengths of specific mRNAs. We identify a set of mRNAs encoding mitochondrial proteins that are down-regulated starting at the earliest stages of OPMD progression. The down-regulation of these mRNAs correlates with their shortened poly(A) tails and partial rescue of their levels when deadenylation is genetically reduced improves muscle function. Genetic analysis of candidate genes encoding RNA binding proteins using the Drosophila OPMD model uncovers a potential role of a number of them. We focus on the deadenylation regulator Smaug and show that it is expressed in adult muscles and specifically binds to the down-regulated mRNAs. In addition, the first step of the cleavage and polyadenylation reaction, mRNA cleavage, is affected in muscles expressing alanine-expanded PABPN1. We propose that impaired cleavage during nuclear cleavage/polyadenylation is an early defect in OPMD. This defect followed by active deadenylation of specific mRNAs, involving Smaug and the CCR4-NOT deadenylation complex, leads to their destabilization and mitochondrial dysfunction. These results broaden our understanding of the role of mRNA regulation in pathologies and might help to understand the molecular mechanisms underlying neurodegenerative disorders that involve mitochondrial dysfunction. Oculopharyngeal muscular dystrophy is a genetic disease characterized by progressive degeneration of specific muscles, leading to ptosis (eyelid drooping), dysphagia (swallowing difficulties) and proximal limb weakness. The disease results from mutations in a nuclear protein called poly(A) binding protein nuclear 1 that is involved in polyadenylation of messenger RNAs (mRNAs) and poly(A) site selection. To address the molecular mechanisms involved in the disease, we have used two animal models (Drosophila and mouse) that recapitulate the features of this disorder. We show that oculopharyngeal muscular dystrophy pathogenesis depends on defects in poly(A) tail length regulation of specific mRNAs. Because poly(A) tails play an essential role in mRNA stability, these defects result in accelerated decay of these mRNAs. The affected mRNAs encode mitochondrial proteins, and mitochondrial activity is impaired in diseased muscles. These findings have important implications for the development of potential therapies for oculopharyngeal muscular dystrophy, and might be relevant to decipher the molecular mechanisms underlying other disorders that involve mitochondrial dysfunction.
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影响因子：
11.1
作者：
Barbezier, Nicolas;Chartier, Aymeric;Bidet, Yannick;Buttstedt, Anja;Voisset, Cecile;Galons, Herve;Blondel, Marc;Schwarz, Elisabeth;Simonelig, Martine
通讯作者：
Simonelig, Martine
影响因子：
11.4
作者：
BIENROTH, S;KELLER, W;WAHLE, E
通讯作者：
WAHLE, E
影响因子：
11.4
作者：
Chartier, Aymeric;Benoit, Beatrice;Simonelig, Martine
通讯作者：
Simonelig, Martine
影响因子：
3.5
作者：
Calado, A;Tomé, FMS;Carmo-Fonseca, M
通讯作者：
Carmo-Fonseca, M
影响因子：
3.5
作者：
Apponi, Luciano H.;Leung, Sara W.;Pavlath, Grace K.
通讯作者：
Pavlath, Grace K.