MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain
Marianne Goodwin,
Apoorva Mohan,
Ranjan Batra,
Kuang-Yung Lee,
Konstantinos Charizanis,
Francisco José Fernández Gómez,
Sabiha Eddarkaoui,
Nicolas Sergeant,
Luc Buée,
Takashi Kimura,
H. Brent Clark,
Joline Dalton,
Kenji Takamura,
Sebastien M. Weyn-Vanhentenryck,
Chaolin Zhang,
Tammy Reid,
Laura P.W. Ranum,
John W. Day,
Maurice S. Swanson
Affiliations
Marianne Goodwin
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA
Apoorva Mohan
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA
Ranjan Batra
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA
Kuang-Yung Lee
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA
Konstantinos Charizanis
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA
Francisco José Fernández Gómez
Inserm UMR S1172, Alzheimer and Tauopathies, Université Lille Nord de France, Centre Jean-Pierre Aubert, 1 Place Verdun, 59045 Lille, France
Sabiha Eddarkaoui
Inserm UMR S1172, Alzheimer and Tauopathies, Université Lille Nord de France, Centre Jean-Pierre Aubert, 1 Place Verdun, 59045 Lille, France
Nicolas Sergeant
Inserm UMR S1172, Alzheimer and Tauopathies, Université Lille Nord de France, Centre Jean-Pierre Aubert, 1 Place Verdun, 59045 Lille, France
Luc Buée
Inserm UMR S1172, Alzheimer and Tauopathies, Université Lille Nord de France, Centre Jean-Pierre Aubert, 1 Place Verdun, 59045 Lille, France
Takashi Kimura
Division of Neurology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan
H. Brent Clark
Departments of Laboratory Medicine and Pathology, Neurology, Neurosurgery, and Genetics, Cell Biology, and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Joline Dalton
Departments of Laboratory Medicine and Pathology, Neurology, Neurosurgery, and Genetics, Cell Biology, and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Kenji Takamura
Departments of Laboratory Medicine and Pathology, Neurology, Neurosurgery, and Genetics, Cell Biology, and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Sebastien M. Weyn-Vanhentenryck
Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA
Chaolin Zhang
Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA
Tammy Reid
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA
Laura P.W. Ranum
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA
John W. Day
Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Palo Alto, CA 94305, USA
Maurice S. Swanson
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA
For some neurological disorders, disease is primarily RNA mediated due to expression of non-coding microsatellite expansion RNAs (RNAexp). 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 RNAexp in the DM brain and introduce a powerful experimental tool to evaluate RNA-mediated toxicity in other expansion diseases.
