title: MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain.
abstract: For some neurological disorders, disease is primarily RNA mediated due to expression of non-coding microsatellite expansion RNAs (RNA(exp)). Toxicity is thought to result from enhanced binding of proteins to these expansions and depletion from their normal cellular targets. However, experimental evidence for this sequestration model is lacking. Here, we use HITS-CLIP and pre-mRNA processing analysis of human control versus myotonic dystrophy (DM) brains to provide compelling evidence for this RNA toxicity model. MBNL2 binds directly to DM repeat expansions in the brain, resulting in depletion from its normal RNA targets with downstream effects on alternative splicing and polyadenylation. Similar RNA processing defects were detected in Mbnl compound-knockout mice, highlighted by dysregulation of Mapt splicing and fetal tau isoform expression in adults. These results demonstrate that MBNL proteins are directly sequestered by RNA(exp) in the DM brain and introduce a powerful experimental tool to evaluate RNA-mediated toxicity in other expansion diseases.
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: Goodwin
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Apoorva
authors.initials: A
authors.lastname: Mohan
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Batra
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA; Department of Neurology, Chang Gung Memorial Hospital, Keelung 20401, Taiwan.
authors.forename: Kuang-Yung
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA; InSiliGen LLC, Gainesville, FL 32606, USA.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Charizanis
authors.affiliation: Inserm UMR S1172, Alzheimer and Tauopathies, Université Lille Nord de France, Centre Jean-Pierre Aubert, 1 Place Verdun, 59045 Lille, France.
authors.forename: Francisco José
authors.initials: FJ
authors.lastname: Fernández Gómez
authors.affiliation: Inserm UMR S1172, Alzheimer and Tauopathies, Université Lille Nord de France, Centre Jean-Pierre Aubert, 1 Place Verdun, 59045 Lille, France.
authors.forename: Sabiha
authors.initials: S
authors.lastname: Eddarkaoui
authors.affiliation: Inserm UMR S1172, Alzheimer and Tauopathies, Université Lille Nord de France, Centre Jean-Pierre Aubert, 1 Place Verdun, 59045 Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
authors.affiliation: Inserm UMR S1172, Alzheimer and Tauopathies, Université Lille Nord de France, Centre Jean-Pierre Aubert, 1 Place Verdun, 59045 Lille, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: Division of Neurology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Departments of Laboratory Medicine and Pathology, Neurology, Neurosurgery, and Genetics, Cell Biology, and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: H Brent
authors.initials: HB
authors.lastname: Clark
authors.affiliation: Departments of Laboratory Medicine and Pathology, Neurology, Neurosurgery, and Genetics, Cell Biology, and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Joline
authors.initials: J
authors.lastname: Dalton
authors.affiliation: Departments of Laboratory Medicine and Pathology, Neurology, Neurosurgery, and Genetics, Cell Biology, and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takamura
authors.affiliation: Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
authors.forename: Sebastien M
authors.initials: SM
authors.lastname: Weyn-Vanhentenryck
authors.affiliation: Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
authors.forename: Chaolin
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Tammy
authors.initials: T
authors.lastname: Reid
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Laura P W
authors.initials: LP
authors.lastname: Ranum
authors.affiliation: Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Day
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA. Electronic address: mswanson@ufl.edu.
authors.forename: Maurice S
authors.initials: MS
authors.lastname: Swanson
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018895:Microsatellite Repeats; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing; D022661:RNA, Untranslated / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C499444:MBNL2 protein, human; C479922:Mbnl1 protein, mouse; D022661:RNA, Untranslated; D016601:RNA-Binding Proteins; D016875:tau Proteins