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

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


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 RNAexpin the DM brain and introduce a powerful experimental tool to evaluate RNA-mediated toxicity in other expansion diseases.

Original languageEnglish (US)
Pages (from-to)1159-1168
Number of pages10
JournalCell reports
Issue number7
StatePublished - Aug 18 2015

Bibliographical note

Funding Information:
We thank J. Lewis for discussions on tauopathies, UF Research Computing for computational resources, and J. Cleary and E. Wang for comments on the manuscript. This study was supported by grants from the NIH (AR046799 and NS058901, to M.S.S.), INSERM (to L.B. and N.S.), CNRS (to L.B.), France Alzheimer and AFM (to N.S.), DN2M and ANR NeuroSplice (to L.B., N.S., F.J.F.G., and S.E.), LabEx and DISTALZ (to L.B., N.S., and S.E.), and the University of Lille, CHR of Lille and Region Nord Pas-de Calais (to N.S.).

Publisher Copyright:
© 2015 The Authors.

Copyright 2017 Elsevier B.V., All rights reserved.


Dive into the research topics of 'MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain'. Together they form a unique fingerprint.

Cite this