Review -- fly models of Myotonic Dustrophy Type 1

Souidi A, Zmojdzian M, Jagla K. Dissecting Pathogenetic Mechanisms and Therapeutic Strategies in Drosophila Models of Myotonic Dystrophy Type 1. Int J Mol Sci. 2018 Dec 18;19(12). PMID: 30567354; PMCID: PMC6321436.

From the abstract: "... Here we provide an overview of insights gained from fruit fly DM1 models, either: (i) fundamental with particular focus on newly identified gene deregulations and their link with DM1 symptoms; or (ii) applied via genetic modifiers and drug screens to identify promising therapeutic targets. ..."

Fig. 1 from Souidi et al. 2018

Review highlights role of zebrafish and Drosophila studies in understanding muscular dystrophies

Plantié E, Migocka-Patrzałek M, Daczewska M, Jagla K. Model organisms in the fight against muscular dystrophy: lessons from drosophila and Zebrafish. Molecules. 2015 Apr 9;20(4):6237-53. PMID: 25859781.

From the abstract: "Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. More than 30 types of MD have been described so far; those most thoroughly studied are Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1) and congenital MDs. ... To improve our knowledge of how MD-caused muscle defects arise and to find efficacious therapeutic treatments, different animal models have been generated and applied. Among these, simple non-mammalian Drosophila and zebrafish models have proved most useful. This review discusses how zebrafish and Drosophila MD have helped to identify genetic determinants of MDs and design innovative therapeutic strategies with a special focus on DMD, DM1 and congenital MDs."

Treatment of Drosophila model of DM1 with pentamidine reverses cellular and organismal phenotypes

Chakraborty M, Selma-Soriano E, Magny E, Couso JP, Pérez-Alonso M, Charlet-Berguerand N, Artero R, Llamusi B. Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction. Dis Model Mech. 2015 Dec;8(12):1569-78. PMID: 26515653; PMCID: PMC4728315.

From the abstract: "Up to 80% of individuals with myotonic dystrophy type 1 (DM1) will develop cardiac abnormalities at some point during the progression of their disease, the most common of which is heart blockage ... Such blockage is characterized by conduction defects and supraventricular and ventricular tachycardia, and carries a high risk of sudden cardiac death. ... Here, we describe the characterization of the heart phenotype in a Drosophila model expressing pure expanded CUG repeats under the control of the cardiomyocyte-specific driver GMH5-Gal4. ... As a proof of concept that the fly heart model can be used for in vivo testing of promising therapeutic compounds, we fed flies with pentamidine, a compound previously described to improve DM1 phenotypes. Pentamidine not only released Muscleblind from the CUG RNA repeats and reduced ribonuclear formation in the Drosophila heart, but also rescued heart arrhythmicity and contractility, and improved fly survival in animals expressing 250 CUG repeats."

Drosophila model used in study related to myotonic dystrophy type 1

Wong CH, Nguyen L, Peh J, Luu LM, Sanchez JS, Richardson SL, Tuccinardi T, Tsoi H, Chan WY, Chan HY, Baranger AM, Hergenrother PJ, Zimmerman SC. Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor. J Am Chem Soc. 2014 Apr 30;136(17):6355-61. PMID: 24702247; PMCID: PMC4015652.

From the abstract: "A working hypothesis for the pathogenesis of myotonic dystrophy type 1 (DM1) involves the aberrant sequestration of an alternative splicing regulator, MBNL1, by expanded CUG repeats, r(CUG)(exp). It has been suggested that a reversal of the myotonia and potentially other symptoms of the DM1 disease can be achieved by inhibiting the toxic MBNL1-r(CUG)(exp) interaction. Using rational design, we discovered an RNA-groove binding inhibitor (ligand 3) that contains two triaminotriazine units connected by a bisamidinium linker. ... Importantly, suppression of r(CUG)(exp) RNA-induced toxicity in a DM1 Drosophila model was observed after treatment with ligand 3. These results suggest ligand 3 as a lead for the treatment of DM1."

New fly model of myotonic dystrophy type 2

Yu Z, Goodman LD, Shieh SY, Min M, Teng X, Zhu Y, Bonini NM. A fly model for the CCUG-repeat expansion of myotonic dystrophy type 2 reveals a novel interaction with MBNL1. Hum Mol Genet. 2015 Feb 15;24(4):954-62. PMID: 25305073.

From the abstract: "Expanded non-coding RNA repeats of CUG and CCUG are the underlying genetic causes for myotonic dystrophy type 1 (DM1) and type 2 (DM2), respectively. A gain-of-function of these pathogenic repeat expansions is mediated at least in part by their abnormal interactions with RNA-binding proteins such as MBNL1 and resultant loss of activity of these proteins. To study pathogenic mechanisms of CCUG-repeat expansions in an animal model, we created a fly model of DM2 that expresses pure, uninterrupted CCUG-repeat expansions ranging from 16 to 720 repeats in length. We show that this fly model for DM2 recapitulates key features of human DM2 including RNA repeat-induced toxicity, ribonuclear foci formation and changes in alternative splicing. ... Our results suggest a novel mechanism for interaction between the pathogenic RNA repeat expansions of myotonic dystrophy and MBNL1."

Drosophila myotonic dystrophy model responds to drug used to treat human patients with the condition

Chakraborty M, Selma-Soriano E, Magny E, Couso JP, Pérez-Alonso M, Charlet-Berguerand N, Artero R, Llamusi B. Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction. Dis Model Mech. 2015 Oct 29. PMID: 26515653.

From the abstract: "Up to 80% of myotonic dystrophy type 1 (DM1) patients will develop cardiac abnormalities ... very few animal model studies have focused on the heart dysfunction in DM1. Here, we describe the characterization of the heart phenotype in a Drosophila model expressing pure expanded CUG repeats under the control of the cardiomyocyte-specific driver GMH5-Gal4. ... Similarly to what has been reported in human DM1 patients, heart-specific expression of toxic RNA resulted in reduced survival, increased arrhythmia, altered diastolic and systolic function ... As a proof of concept that the fly heart model can be used for in vivo testing of promising therapeutic compounds, we fed flies with pentamidine, a compound previously described to improve DM1 phenotypes. Pentamidine not only released Muscleblind and reduced ribonuclear formation in the Drosophila heart but rescued heart arrhythmicity and contractility, and improved fly survival in animals expressing 250 CUG repeats."

New fly model related to myotonic dystrophy type 1 (DM1)

Bargiela A, Cerro-Herreros E, Fernandez-Costa JM, Vilchez JJ, Llamusi B, Artero R. Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model. Dis Model Mech. 2015 Jul 1;8(7):679-90. PMID: 26092529.

From the abstract: "Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. ... results were validated in skeletal muscle biopsies from DM1 patients ... and also in DM1 myoblasts ... These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis."

'Spliceosensor' in flies for high-throughput screening related to myotonic dystrophy

García-Alcover I, Colonques-Bellmunt J, Garijo R, Tormo JR, Artero R, Alvarez-Abril MC, López Castel A, Pérez Alonso M. Development of a Drosophila melanogaster spliceosensor system for in vivo high-throughput screening in myotonic dystrophy type 1. Dis Model Mech. 2014 Sep 19. pii: dmm.016592. PMID: 25239918.

From the abstract: "... This powerful Drosophila-based screening tool might also be applied in other  disease models displaying abnormal alternative splicing, thus offering myriad uses in drug discovery."

Fly model of myotonic dystrophy type 1

Picchio L, Plantie E, Renaud Y, Poovthumkadavil P, Jagla K. Novel Drosophila model of myotonic dystrophy type 1: phenotypic characterization and genome-wide view of altered gene expression. Hum Mol Genet. 2013 Jul 15;22(14):2795-810. PMID: 23525904.

Screen in fly model of the myopathy Myotonic Dystrophy Type 1

This study related to Myotonic Dystrophy Type 1 crosses the bridge from fly screen (eye phenotype readout) to mammalian cell follow-up studies.

de Haro M, Al-Ramahi I, Jones KR, Holth JK, Timchenko LT, Botas J. Smaug/SAMD4A Restores Translational Activity of CUGBP1 and Suppresses CUG-Induced Myopathy. PLoS Genet. 2013 Apr;9(4):e1003445. PMID: 23637619; PMCID: PMC3630084.

New Fly Model of Myotonic Dystrophy. Recent Report.

Picchio L, Plantie E, Renaud Y, Poovthumkadavil P, Jagla K. Novel Drosophila model of myotonic dystrophy type 1: phenotypic characterization and genome-wide view of altered gene expression. Hum Mol Genet. 2013 Apr 3. PubMed PMID: 23525904.

From the abstract: "we found the calcium pump dSERCA as a Mbl splice target and show that the membrane dSERCA isoform is sufficient to rescue a DM1-induced hypercontraction phenotype in a Drosophila model."

Myotonic Dystrophy Type I. Recent report.

Llamusi B, Bargiela A, Fernandez-Costa JM, Garcia-Lopez A, Klima R, Feiguin F, Artero R. Muscleblind, BSF and TBPH are mislocalized in the muscle sarcomere of a Drosophila myotonic dystrophy model. Dis Model Mech. 2012 Nov 1. PubMed PMID: 23118342.