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*

*此作品的通信作者

研究成果: 期刊稿件文章同行評審

109 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
頁(從 - 到)1159-1168
頁數10
期刊Cell Reports
12
發行號7
DOIs
出版狀態已出版 - 18 08 2015
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© 2015 The Authors.

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