Muscleblind, BSF and TBPH are mislocalized in the muscle sarcomere of a Drosophila myotonic dystrophy model.
Muscleblind, BSF and TBPH are mislocalized in the muscle sarcomere of a Drosophila myotonic dystrophy model.
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DOI：
10.1242/dmm.009563
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发表时间：
2013-01
影响因子：
4.3
通讯作者：
Artero R
中科院分区：
文献类型：
--
作者：
Llamusi B;Bargiela A;Fernandez-Costa JM;Garcia-Lopez A;Klima R;Feiguin F;Artero R
强直性肌营养不良1型（Myotonic dystrophy type 1，DM 1）是由DMPK基因3′ UTR的CTG三核苷酸重复序列病理性扩增引起的遗传性疾病。在DMPK转录物中，CUG扩增将RNA结合蛋白隔离到核灶中，包括转录因子和选择性剪接调节因子如MBNL 1。MBNL 1螯合与DM 1的关键特征相关。然而，DM 1中许多分子和组织学改变背后的基础仍不清楚。为了帮助确定新的致病成分的疾病，我们进行了遗传筛选，使用果蝇模型DM 1，表达480中断CTG重复，i（CTG）480，和1215转基因RNA干扰（RNAi）飞线的集合。在鉴定的34种修饰剂中，两种RNA结合蛋白TBPH（人TAR DNA结合蛋白43或TDP-43的同系物）和BSF（Bicoid稳定因子;人LRPPRC的同系物）特别令人感兴趣。这些因素修改i（CTG）480表型在苍蝇的眼睛和翅膀，TBPH沉默也抑制CTG诱导的飞行肌肉缺陷。在果蝇飞行肌中，在肌节带中检测到TBPH、BSF和MBNL 1的果蝇直系同源物Muscleblind（Mbl）。i（CTG）480的表达导致这些蛋白质的肌节模式的变化，这可以通过与人MBNL 1共表达来恢复。上位性研究表明，Mbl沉默足以诱导TBPH和BSF蛋白在肌肉中的亚细胞再分布，这模拟了i（CTG）480表达的作用。这些结果提供了TBPH和BSF作为MBL介导的CTG毒性的靶的第一描述，并且它们表明这些蛋白在DM 1肌肉病理中的重要作用。
Myotonic dystrophy type 1 (DM1) is a genetic disease caused by the pathological expansion of a CTG trinucleotide repeat in the 3′ UTR of the DMPK gene. In the DMPK transcripts, the CUG expansions sequester RNA-binding proteins into nuclear foci, including transcription factors and alternative splicing regulators such as MBNL1. MBNL1 sequestration has been associated with key features of DM1. However, the basis behind a number of molecular and histological alterations in DM1 remain unclear. To help identify new pathogenic components of the disease, we carried out a genetic screen using a Drosophila model of DM1 that expresses 480 interrupted CTG repeats, i(CTG)480, and a collection of 1215 transgenic RNA interference (RNAi) fly lines. Of the 34 modifiers identified, two RNA-binding proteins, TBPH (homolog of human TAR DNA-binding protein 43 or TDP-43) and BSF (Bicoid stability factor; homolog of human LRPPRC), were of particular interest. These factors modified i(CTG)480 phenotypes in the fly eye and wing, and TBPH silencing also suppressed CTG-induced defects in the flight muscles. In Drosophila flight muscle, TBPH, BSF and the fly ortholog of MBNL1, Muscleblind (Mbl), were detected in sarcomeric bands. Expression of i(CTG)480 resulted in changes in the sarcomeric patterns of these proteins, which could be restored by coexpression with human MBNL1. Epistasis studies showed that Mbl silencing was sufficient to induce a subcellular redistribution of TBPH and BSF proteins in the muscle, which mimicked the effect of i(CTG)480 expression. These results provide the first description of TBPH and BSF as targets of Mbl-mediated CTG toxicity, and they suggest an important role of these proteins in DM1 muscle pathology.
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影响因子：
3.5
作者：
Ho, TH;Bundman, D;Cooper, TA
通讯作者：
Cooper, TA
影响因子：
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Armstrong, Richard A.;Cairns, Nigel J.
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Cairns, Nigel J.
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1.5
作者：
García-Casado, Z;Artero, RD;Pérez-Alonso, M
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Pérez-Alonso, M
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Baylies, MK
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作者：
Gregory, Stephen L.;Shandala, Tetyana;Saint, Robert
通讯作者：
Saint, Robert