Maury Yves, Poydenot Pauline, Brinon Benjamin, Lesueur Lea, Gide Jacqueline, Roquevière Sylvain, Côme Julien, Polvèche Hélène, Auboeuf Didier, Alexandre Denis Jérome, Pietu Geneviève, Furling Denis, Lechuga Marc, Baghdoyan Sandrine, Peschanski Marc, Martinat Cécile
CECS, I-STEM, AFM, 91100 Corbeil-Essonnes, France.
INSERM, UMR 861, UEVE, ISTEM, AFM, 91100 Corbeil-Essonnes, France.
iScience. 2019 Jan 25;11:258-271. doi: 10.1016/j.isci.2018.12.019. Epub 2018 Dec 27.
There is currently no treatment for myotonic dystrophy type 1 (DM1), the most frequent myopathy of genetic origin. This progressive neuromuscular disease is caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors, resulting in alternative splicing misregulation. By combining human mutated pluripotent stem cells and phenotypic drug screening, we revealed that cardiac glycosides act as modulators for both upstream nuclear aggregations of DMPK mRNAs and several downstream alternative mRNA splicing defects. However, these occurred at different drug concentration ranges. Similar biological effects were recorded in a DM1 mouse model. At the mechanistic level, we demonstrated that this effect was calcium dependent and was synergic with inhibition of the ERK pathway. These results further underscore the value of stem-cell-based assays for drug discovery in monogenic diseases.
目前尚无针对1型强直性肌营养不良症（DM1）的治疗方法，这是最常见的遗传性肌病。这种进行性神经肌肉疾病由含有扩展CUG重复序列的核滞留RNA引起。这些毒性RNA改变了RNA剪接因子的活性，导致选择性剪接失调。通过将人类突变多能干细胞与表型药物筛选相结合，我们发现强心苷可作为DMPK mRNA上游核聚集和几种下游选择性mRNA剪接缺陷的调节剂。然而，这些作用发生在不同的药物浓度范围内。在DM1小鼠模型中也记录到了类似的生物学效应。在机制层面，我们证明这种效应依赖于钙，并且与ERK途径的抑制具有协同作用。这些结果进一步强调了基于干细胞的检测在单基因疾病药物发现中的价值。
