In vivo discovery of a peptide that prevents CUG-RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models

Amparo Garcia-Lopez; Beatriz Llamusi; Mar Orzaez; Enrique Perez-Paya; Ruben D. Artero

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In vivo discovery of a peptide that prevents CUG-RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models

机译：在强直性营养不良模型中体内预防CUG-RNA发夹形成并逆转RNA毒性的肽的体内发现

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Myotonic dystrophy type 1 (DM1) is caused by the expansion of noncoding CTG repeats in the dystrophia myotonica-protein kinase gene. Mutant transcripts form CUG hairpins that sequester RNA-binding factors into nuclear foci, including Muscleblind-like-1 protein (MBNL1), which regulate alternative splicing and gene expression. To identify molecules that target toxic CUG transcripts in vivo, we performed a positional scanning combinatorial peptide library screen using a Drosophila model of DM1. The screen identified a D-amino acid hexapeptide (ABP1) that reduced CUG foci formation and suppressed CUG-induced lethality and muscle degeneration when administered orally. Transgenic expression of natural, L-ami-no acid ABP1 analogues reduced CUG-induced toxicity in fly eyes and muscles. Furthermore, ABP1 reversed muscle histopathology and splicing misregulation of MBNL1 targets in DM1 model mice. In vitro, ABP1 bound to CUG hairpins and induced a switch to a single-stranded conformation. Our findings demonstrate that ABP1 shows antimyotonic dystrophy activity by targeting the core of CUG toxicity.

机译：1型肌强直性营养不良（DM1）是由肌营养不良症肌强直蛋白激酶基因中非编码CTG重复序列的扩增引起的。突变体转录本形成CUG发夹，将RNA结合因子螯合入核灶，包括Muscleblind-like-1蛋白（MBNL1），后者调节其他剪接和基因表达。为了鉴定体内靶向有毒CUG转录物的分子，我们使用果蝇DM1模型进行了位置扫描组合肽库筛选。该筛查确定了一种D-氨基酸六肽（ABP1），可减少CUG灶的形成并抑制CUG诱导的致死性和肌肉变性（口服）。天然L-氨基酸ABP1类似物的转基因表达减少了CUG诱导的蝇眼和肌肉毒性。此外，ABP1逆转了DM1模型小鼠的肌肉组织病理学和MBNL1目标的剪接失调。在体外，ABP1与CUG发夹结合并诱导转换为单链构象。我们的发现表明，ABP1通过靶向CUG毒性的核心表现出抗强直性营养不良的活性。

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来源
《Proceedings of the National Academy of Sciences of the United States of America》 |2011年第29期|p.11866-11871|共6页
作者
Amparo Garcia-Lopez; Beatriz Llamusi; Mar Orzaez; Enrique Perez-Paya; Ruben D. Artero;
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作者单位

Department of Genetics, University of Valencia, Burjassot E-46100, Spain;

Department of Genetics, University of Valencia, Burjassot E-46100, Spain;

Peptide and Protein Chemistry Laboratory, Centro de Investigacion Principe Felipe, Valencia E-46012, Spain;

Peptide and Protein Chemistry Laboratory, Centro de Investigacion Principe Felipe, Valencia E-46012, Spain Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Cientfficas, Valencia E-46010, Spain;

Department of Genetics, University of Valencia, Burjassot E-46100, Spain;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
中图分类
关键词
disease model; drug discovery; non-coding rna disease; medicinal chemistry; rna secondary structure;

机译：疾病模型药物发现;非编码性RNA疾病;药物化学RNA二级结构;

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专利

1. Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model [J] . deLorimier Elaine, Coonrod Leslie A., Copperman Jeremy, Nucleic Acids Research . 2014,第20期

机译：对有毒CUG RNA的修饰可诱导结构稳定性，在强直性营养不良性细胞模型中挽救错剪并降低强直性营养不良性斑马鱼模型中的毒性
2. Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model [J] . Alex Taber, Elaine deLorimier, Emily E. Reister, Nucleic acids research . 2014,第20期

机译：对有毒CUG RNA的修饰可诱导结构稳定性，在强直性营养不良性细胞模型中挽救错剪并降低强直性营养不良性斑马鱼模型中的毒性
3. Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model [J] . Alex Taber, Elaine deLorimier, Emily E. Reister, Nucleic acids research . 2014,第20期

机译：对有毒CUG RNA的修饰可诱导结构稳定性，在强直性营养不良性细胞模型中挽救错剪并降低强直性营养不良性斑马鱼模型中的毒性
4. De novo design of peptides containing L-alpha-nucleobase amino acids and their recognition of hairpin RNA [C] . Hideo Miyanishi, Tsuyoshi Takahashi, Akihiko Ueno, European Peptide Symposium . 2002

机译：De Novo设计含有L-α-核碱基氨基酸的肽及其发夹RNA的识别
5. CCUG repeat toxicity in myotonic dystrophy type 2 (DM2). [D] . Margolis, Jamie Marie. 2008

机译：CCUG对2型强直性肌营养不良症（DM2）重复毒性。
6. In vivo discovery of a peptide that prevents CUG–RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models [O] . Amparo García-López, Beatriz Llamusí, Mar Orzáez, 2011

机译：体内发现一种防止强直性营养不良模型中CUG-RNA发夹形成并逆转RNA毒性的肽
7. In vivo discovery of a peptide that prevents CUG-RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models [O] . García-López, Amparo, Llamusí, Beatriz, Orzáez, Mar, 2011

机译：在强直性营养不良模型中体内预防CUG-RNA发夹形成并逆转RNA毒性的肽的体内发现

In vivo discovery of a peptide that prevents CUG-RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models

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