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.
Bibliographical noteFunding 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.).
© 2015 The Authors.
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