Goodwin Marianne, Mohan Apoorva, Batra Ranjan, Lee Kuang-Yung, Charizanis Konstantinos, Fernández Gómez Francisco José, Eddarkaoui Sabiha, Sergeant Nicolas, Buée Luc, Kimura Takashi, Clark H Brent, Dalton Joline, Takamura Kenji, Weyn-Vanhentenryck Sebastien M, Zhang Chaolin, Reid Tammy, Ranum Laura P W, Day John W, Swanson Maurice S
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 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.
Cell Rep. 2015 Aug 18;12(7):1159-68. doi: 10.1016/j.celrep.2015.07.029. Epub 2015 Aug 6.
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.
对于某些神经疾病，疾病主要由RNA介导，这是由于非编码微卫星扩展RNA（RNA(exp)）的表达所致。毒性被认为是蛋白质与这些扩展序列增强结合以及从其正常细胞靶点耗竭的结果。然而，这种隔离模型缺乏实验证据。在这里，我们使用人类对照与强直性肌营养不良（DM）大脑的HITS-CLIP和前体mRNA加工分析，为这种RNA毒性模型提供了令人信服的证据。MBNL2直接与大脑中的DM重复扩展序列结合，导致其从正常RNA靶点耗竭，对可变剪接和聚腺苷酸化产生下游影响。在Mbnl复合敲除小鼠中检测到类似的RNA加工缺陷，其突出表现为成年小鼠中Mapt剪接失调和胎儿tau异构体表达异常。这些结果表明，在DM大脑中，MBNL蛋白被RNA(exp)直接隔离，并引入了一种强大的实验工具来评估其他扩展疾病中RNA介导的毒性。
