期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：26
页码：8041-8045
DOI：10.1073/pnas.1422273112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceInherited multisystemic diseases, myotonic dystrophies type 1 (DM1) and type 2 (DM2), are caused by long CUG and CCUG RNA repeats. The mutant RNA CCUG repeats should be degraded after intron excision; however, this RNA accumulates in cells, leading to pathology. Although mutant RNAs may be degraded with synthetic oligonucleotides, the identification of a cause of the increased stability of CUG and CCUG RNAs would help to improve the efficiency of their degradation. We found that the reduction of RNA helicase p68 in skeletal muscle biopsies of DM1 and DM2 patients contributes to the delay of degradation of the mutant RNAs. Our work suggests RNA helicase p68 as a therapeutic target in DM, correction of which improves degradation of the mutant RNAs, reducing DM pathology. 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.
