Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5
Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5
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DOI：
10.1073/pnas.1422273112
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发表时间：
2015-06-30
影响因子：
11.1
通讯作者：
Timchenko, Lubov
中科院分区：
文献类型：
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作者：
Jones, Karlie;Wei, Christina;Timchenko, Lubov
强直性肌营养不良 1 型 (DM1) 和 2 型 (DM2) 是神经肌肉疾病，由 CUG 和 CCUG RNA 在有毒聚集物中积累引起。在这里，我们报道了两种类型的DM中突变RNA稳定性的增加是由于RNA解旋酶p68的缺陷引起的。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。 DM1 和 DM2 骨骼肌活检中 p68 的蛋白水平降低。在 DM1/2 细胞中传递 p68 会导致突变体 RNA 的降解，而在 DM1 小鼠模型的骨骼肌中传递 p68 可减少骨骼肌肌病和萎缩。我们的研究表明，p68 的校正可能会降低 DM1 和 DM2 中突变 RNA 的毒性。
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 DMis 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.