title: MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1.
abstract: Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG expansion in the 3' UTR of the dystrophia myotonica protein kinase (DMPK) gene. It has been hypothesized that the pathogenesis in DM1 is triggered by a toxic gain of function of the expanded DMPK RNA. This expanded RNA is retained in nuclear foci where it sequesters and induces alterations in the levels of RNA-binding proteins (RNA-BP). To model DM1 and study the implication of RNA-BP in CUG-induced toxicity, we have generated a Drosophila DM1 model expressing a non-coding mRNA containing 480 interrupted CUG repeats; i.e. [(CUG)20CUCGA]24. This (iCUG)480 transcript accumulates in nuclear foci and its expression leads to muscle wasting and degeneration in Drosophila. We also report that altering the levels of two RNA-BP known to be involved in DM1 pathogenesis, MBNL1 and CUGBP1, modify the (iCUG)480 degenerative phenotypes. Expanded CUG-induced toxicity in Drosophila is suppressed when MBNL1 expression levels are increased, and enhanced when MBNL1 levels are reduced. In addition, (iCUG)480 also causes a decrease in the levels of soluble MBNL1 that is sequestered in the CUG-containing nuclear foci. In contrast, increasing the levels of CUGBP1 worsens (iCUG)480-induced degeneration even though CUGBP1 distribution is not altered by the expression of the expanded triplet repeat. Our data supports a mechanism for DM1 pathogenesis in which decreased levels of MBNL and increased levels of CUGBP mediate the RNA-induced toxicity observed in DM1. Perhaps more importantly, they also provide proof of the principle that CUG-induced muscle toxicity can be suppressed.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: María
authors.initials: M
authors.lastname: de Haro
authors.forename: Ismael
authors.initials: I
authors.lastname: Al-Ramahi
authors.forename: Beatrice
authors.initials: B
authors.lastname: De Gouyon
authors.forename: Lubna
authors.initials: L
authors.lastname: Ukani
authors.forename: Alberto
authors.initials: A
authors.lastname: Rosa
authors.forename: Nuno André
authors.initials: NA
authors.lastname: Faustino
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ashizawa
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Cooper
authors.forename: Juan
authors.initials: J
authors.lastname: Botas
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015152:Blotting, Northern; D000067879:CELF1 Protein; D002467:Cell Nucleus / Q000378:metabolism; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D005123:Eye / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D017403:In Situ Hybridization; D008855:Microscopy, Electron, Scanning; D009132:Muscles / Q000378:metabolism / Q000648:ultrastructure; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D000067879:CELF1 Protein; C102843:CELF1 protein, human; C493663:MBNL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins