Expanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic Dystrophy type 1-like phenotypes and activate autophagocytosis genes

Abstract Myotonic dystrophies (DM1–2) are neuromuscular genetic disorders caused by the pathological expansion of untranslated microsatellites. DM1 and DM2, are caused by expanded CTG repeats in the 3′UTR of the DMPK gene and CCTG repeats in the first intron of the CNBP gene, respectively. Mutant RN...

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Autores principales:	Estefania Cerro-Herreros, Mouli Chakraborty, Manuel Pérez-Alonso, Rubén Artero, Beatriz Llamusí
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/191767f7e9c745faa665585c3f3653f7
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spelling	oai:doaj.org-article:191767f7e9c745faa665585c3f3653f72021-12-02T12:32:55ZExpanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic Dystrophy type 1-like phenotypes and activate autophagocytosis genes10.1038/s41598-017-02829-32045-2322https://doaj.org/article/191767f7e9c745faa665585c3f3653f72017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02829-3https://doaj.org/toc/2045-2322Abstract Myotonic dystrophies (DM1–2) are neuromuscular genetic disorders caused by the pathological expansion of untranslated microsatellites. DM1 and DM2, are caused by expanded CTG repeats in the 3′UTR of the DMPK gene and CCTG repeats in the first intron of the CNBP gene, respectively. Mutant RNAs containing expanded repeats are retained in the cell nucleus, where they sequester nuclear factors and cause alterations in RNA metabolism. However, for unknown reasons, DM1 is more severe than DM2. To study the differences and similarities in the pathogenesis of DM1 and DM2, we generated model flies by expressing pure expanded CUG ([250]×) or CCUG ([1100]×) repeats, respectively, and compared them with control flies expressing either 20 repeat units or GFP. We observed surprisingly severe muscle reduction and cardiac dysfunction in CCUG-expressing model flies. The muscle and cardiac tissue of both DM1 and DM2 model flies showed DM1-like phenotypes including overexpression of autophagy-related genes, RNA mis-splicing and repeat RNA aggregation in ribonuclear foci along with the Muscleblind protein. These data reveal, for the first time, that expanded non-coding CCUG repeat-RNA has similar in vivo toxicity potential as expanded CUG RNA in muscle and heart tissues and suggests that specific, as yet unknown factors, quench CCUG-repeat toxicity in DM2 patients.Estefania Cerro-HerrerosMouli ChakrabortyManuel Pérez-AlonsoRubén ArteroBeatriz LlamusíNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Estefania Cerro-Herreros Mouli Chakraborty Manuel Pérez-Alonso Rubén Artero Beatriz Llamusí Expanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic Dystrophy type 1-like phenotypes and activate autophagocytosis genes
description	Abstract Myotonic dystrophies (DM1–2) are neuromuscular genetic disorders caused by the pathological expansion of untranslated microsatellites. DM1 and DM2, are caused by expanded CTG repeats in the 3′UTR of the DMPK gene and CCTG repeats in the first intron of the CNBP gene, respectively. Mutant RNAs containing expanded repeats are retained in the cell nucleus, where they sequester nuclear factors and cause alterations in RNA metabolism. However, for unknown reasons, DM1 is more severe than DM2. To study the differences and similarities in the pathogenesis of DM1 and DM2, we generated model flies by expressing pure expanded CUG ([250]×) or CCUG ([1100]×) repeats, respectively, and compared them with control flies expressing either 20 repeat units or GFP. We observed surprisingly severe muscle reduction and cardiac dysfunction in CCUG-expressing model flies. The muscle and cardiac tissue of both DM1 and DM2 model flies showed DM1-like phenotypes including overexpression of autophagy-related genes, RNA mis-splicing and repeat RNA aggregation in ribonuclear foci along with the Muscleblind protein. These data reveal, for the first time, that expanded non-coding CCUG repeat-RNA has similar in vivo toxicity potential as expanded CUG RNA in muscle and heart tissues and suggests that specific, as yet unknown factors, quench CCUG-repeat toxicity in DM2 patients.
format	article
author	Estefania Cerro-Herreros Mouli Chakraborty Manuel Pérez-Alonso Rubén Artero Beatriz Llamusí
author_facet	Estefania Cerro-Herreros Mouli Chakraborty Manuel Pérez-Alonso Rubén Artero Beatriz Llamusí
author_sort	Estefania Cerro-Herreros
title	Expanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic Dystrophy type 1-like phenotypes and activate autophagocytosis genes
title_short	Expanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic Dystrophy type 1-like phenotypes and activate autophagocytosis genes
title_full	Expanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic Dystrophy type 1-like phenotypes and activate autophagocytosis genes
title_fullStr	Expanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic Dystrophy type 1-like phenotypes and activate autophagocytosis genes
title_full_unstemmed	Expanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic Dystrophy type 1-like phenotypes and activate autophagocytosis genes
title_sort	expanded ccug repeat rna expression in drosophila heart and muscle trigger myotonic dystrophy type 1-like phenotypes and activate autophagocytosis genes
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/191767f7e9c745faa665585c3f3653f7
work_keys_str_mv	AT estefaniacerroherreros expandedccugrepeatrnaexpressionindrosophilaheartandmuscletriggermyotonicdystrophytype1likephenotypesandactivateautophagocytosisgenes AT moulichakraborty expandedccugrepeatrnaexpressionindrosophilaheartandmuscletriggermyotonicdystrophytype1likephenotypesandactivateautophagocytosisgenes AT manuelperezalonso expandedccugrepeatrnaexpressionindrosophilaheartandmuscletriggermyotonicdystrophytype1likephenotypesandactivateautophagocytosisgenes AT rubenartero expandedccugrepeatrnaexpressionindrosophilaheartandmuscletriggermyotonicdystrophytype1likephenotypesandactivateautophagocytosisgenes AT beatrizllamusi expandedccugrepeatrnaexpressionindrosophilaheartandmuscletriggermyotonicdystrophytype1likephenotypesandactivateautophagocytosisgenes
_version_	1718393903816638464

Expanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic Dystrophy type 1-like phenotypes and activate autophagocytosis genes

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