RNA解旋酶p68/DDX5降低1型和2型强直性肌营养不良中的毒性RNA
Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5.
作者信息
Jones Karlie, Wei Christina, Schoser Benedikt, Meola Giovanni, Timchenko Nikolai, Timchenko Lubov
机构信息
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Division of Neurology, Cincinnati Children's Hospital and University of Cincinnati Medical Center, Cincinnati, OH 45219;
出版信息
Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):8041-5. doi: 10.1073/pnas.1422273112. Epub 2015 Jun 15.
Myotonic dystrophies type 1 (DM1) and type 2 (DM2) are neuromuscular diseases, caused by accumulation of CUG and CCUG RNAs in toxic aggregates. Here we report that the increased stability of the mutant RNAs in both types of DM is caused by deficiency of RNA helicase p68. We have identified p68 by studying CCUG-binding proteins associated with degradation of the mutant CCUG repeats. Protein levels of p68 are reduced in DM1 and DM2 biopsied skeletal muscle. Delivery of p68 in DM1/2 cells causes degradation of the mutant RNAs, whereas delivery of p68 in skeletal muscle of DM1 mouse model reduces skeletal muscle myopathy and atrophy. Our study shows that correction of p68 may reduce toxicity of the mutant RNAs in DM1 and in DM2.
1型强直性肌营养不良症（DM1）和2型强直性肌营养不良症（DM2）是神经肌肉疾病，由有毒聚集体中CUG和CCUG RNA的积累引起。在此我们报告，两种类型的强直性肌营养不良症中突变RNA稳定性的增加是由RNA解旋酶p68缺乏所致。我们通过研究与突变CCUG重复序列降解相关的CCUG结合蛋白鉴定出了p68。在DM1和DM2活检骨骼肌中，p68的蛋白水平降低。在DM1/2细胞中递送p68会导致突变RNA降解，而在DM1小鼠模型的骨骼肌中递送p68可减轻骨骼肌肌病和萎缩。我们的研究表明，纠正p68可能会降低DM1和DM2中突变RNA的毒性。
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