title: Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5.
abstract: Myotonic dystrophies type 1 (DM1) and type 2 (DM2) are neuromuscular diseases, caused by accumulation of CUG and CCUG RNAs in toxic aggregates. Here we report that the increased stability of the mutant RNAs in both types of DM is caused by deficiency of RNA helicase p68. We have identified p68 by studying CCUG-binding proteins associated with degradation of the mutant CCUG repeats. Protein levels of p68 are reduced in DM1 and DM2 biopsied skeletal muscle. Delivery of p68 in DM1/2 cells causes degradation of the mutant RNAs, whereas delivery of p68 in skeletal muscle of DM1 mouse model reduces skeletal muscle myopathy and atrophy. Our study shows that correction of p68 may reduce toxicity of the mutant RNAs in DM1 and in DM2.
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Karlie
authors.initials: K
authors.lastname: Jones
authors.affiliation: Division of Neurology, Cincinnati Children's Hospital and University of Cincinnati Medical Center, Cincinnati, OH 45219;
authors.forename: Christina
authors.initials: C
authors.lastname: Wei
authors.affiliation: Friedrich-Baur-Institut, Department of Neurology, Ludwig-Maximilians-Universität, 80336 Munich, Germany;
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
authors.affiliation: Department of Neurology, University of Milan, IRCCS Policlinico San Donato, 20097 Milan, Italy;
authors.forename: Giovanni
authors.initials: G
authors.lastname: Meola
authors.affiliation: Department of Surgery, Cincinnati Children's Hospital and University of Cincinnati Medical Center, Cincinnati, OH 45219.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Timchenko
authors.affiliation: Division of Neurology, Cincinnati Children's Hospital and University of Cincinnati Medical Center, Cincinnati, OH 45219; Lubov.Timchenko@cchmc.org.
authors.forename: Lubov
authors.initials: L
authors.lastname: Timchenko
mesh_terms: D000818:Animals; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000473:pathology; D012313:RNA / Q000235:genetics / Q000302:isolation & purification*
chemical_list: D012313:RNA; C506749:Ddx5 protein, human; D053487:DEAD-box RNA Helicases
keywords: CUG repeats; RNA foci; myotonic dystrophy; p68 RNA helicase