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Cell Rep. 2015 Aug 18;12(7):1159-68. doi: 10.1016/j.celrep.2015.07.029. Epub 2015 Aug 6.

MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain.

Author information

1
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
2
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.
3
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.
4
Inserm UMR S1172, Alzheimer and Tauopathies, Université Lille Nord de France, Centre Jean-Pierre Aubert, 1 Place Verdun, 59045 Lille, France.
5
Division of Neurology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan.
6
Departments of Laboratory Medicine and Pathology, Neurology, Neurosurgery, and Genetics, Cell Biology, and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
7
Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
8
Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Palo Alto, CA 94305, USA.
9
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.

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.

PMID:
26257173
PMCID:
PMC4545389
DOI:
10.1016/j.celrep.2015.07.029
[Indexed for MEDLINE]
Free PMC Article
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