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

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. [Display omitted] •MBNL proteins are directly sequestered by microsatellite expansion RNAs•Toxic RNA expression results in MBNL depletion from its normal RNA targets•MBNL loss leads to fetal patterns of splicing and polyadenylation in the brain•HITS-CLIP provides a tool to validate potential RNA expansion binding proteins In neurological disorders caused by non-coding microsatellite expansions, disease is caused by expression of toxic tandem repeat RNAs. Goodwin et al. show that MBNL2 is directly sequestered by toxic RNAs in the human brain, leading to aberrant splicing and polyadenylation of numerous target RNAs.