Correction of Glycogen Synthase Kinase 3β in Myotonic Dystrophy 1 Reduces the Mutant RNA and Improves Postnatal Survival of DMSXL Mice.
Correction of Glycogen Synthase Kinase 3β in Myotonic Dystrophy 1 Reduces the Mutant RNA and Improves Postnatal Survival of DMSXL Mice.
复制标题
强直性肌营养不良 1 中糖原合酶激酶 3β 的校正减少了突变 RNA 并提高了 DMSXL 小鼠的产后存活率。
DOI：
10.1128/mcb.00155-19
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发表时间：
2019
影响因子：
5.3
通讯作者：
Timchenko,Lubov
中科院分区：
文献类型：
--
作者：
Wang,Mei;Weng,Wen-Chin;Stock,Lauren;Lindquist,Diana;Martinez,Ana;Gourdon,Genevieve;Timchenko,Nikolai;Snape,Mike;Timchenko,Lubov
强直性肌营养不良1型（DM 1）是一种无法治愈的多系统神经肌肉疾病。DM 1的一种可能的治疗方法是纠正DM 1中错误调节的RNA结合蛋白CUGBP 1和MBNL 1。CUGBP 1活性由糖原合成酶激酶3β（GSK 3 β）控制，GSK 3 β在DM 1患者的骨骼肌中升高，并且GSK 3的抑制剂被建议作为治疗分子来校正DM 1中的CUGBP 1活性。在这里，我们描述了用GSK 3的小分子抑制剂tideglusib（TG）校正GSK 3 β，不仅使GSK 3 β-CUGBP 1通路正常化，而且还降低了成人DM 1和先天性DM 1（CDM 1）患者成肌细胞中的MUMPKmRNA。用TG校正DM 1小鼠模型（HSALR小鼠）中的GSK 3 β也降低了含CUG的RNA水平，使许多CUGBP 1和MBNL 1调节的mRNA靶点正常化。我们还发现，GSK 3 β-CUGBP 1通路在DMSXL小鼠的骨骼肌和大脑中异常，表达超过1,000个CUG重复序列，并且用TG纠正该通路可增加出生后存活率并改善DMSXL小鼠的生长和神经运动活性。这些发现表明，GSK 3的抑制剂，如TG，可以通过几种途径纠正DM 1和CDM 1的病理。
Myotonic dystrophy type 1 (DM1) is a multisystem neuromuscular disease without cure. One of the possible therapeutic approaches for DM1 is correction of the RNA-binding proteins CUGBP1 and MBNL1, misregulated in DM1. CUGBP1 activity is controlled by glycogen synthase kinase 3β(GSK3β), which is elevated in skeletal muscle of patients with DM1, and inhibitors of GSK3 were suggested as therapeutic molecules to correct CUGBP1 activity in DM1. Here, we describe that correction of GSK3βwith a small-molecule inhibitor of GSK3, tideglusib (TG), not only normalizes the GSK3β-CUGBP1 pathway but also reduces the mutantDMPKmRNA in myoblasts from patients with adult DM1 and congenital DM1 (CDM1). Correction of GSK3βin a mouse model of DM1 (HSALRmice) with TG also reduces the levels of CUG-containing RNA, normalizing a number of CUGBP1- and MBNL1-regulated mRNA targets. We also found that the GSK3β-CUGBP1 pathway is abnormal in skeletal muscle and brain of DMSXL mice, expressing more than 1,000 CUG repeats, and that the correction of this pathway with TG increases postnatal survival and improves growth and neuromotor activity of DMSXL mice. These findings show that the inhibitors of GSK3, such as TG, may correct pathology in DM1 and CDM1 via several pathways.