Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
JCI Insight. 2020 Sep 17;5(18):137899. doi: 10.1172/jci.insight.137899.
Classical dynamins are large GTPases regulating membrane and cytoskeleton dynamics, and they are linked to different pathological conditions ranging from neuromuscular diseases to encephalopathy and cancer. Dominant dynamin 2 (DNM2) mutations lead to either mild adult onset or severe autosomal dominant centronuclear myopathy (ADCNM). Our objectives were to better understand the pathomechanism of severe ADCNM and test a potential therapy. Here, we created the Dnm2SL/+ mouse line harboring the common S619L mutation found in patients with severe ADCNM and impairing the conformational switch regulating dynamin self-assembly and membrane remodeling. The Dnm2SL/+ mouse faithfully reproduces severe ADCNM hallmarks with early impaired muscle function and force, together with myofiber hypotrophy. It revealed swollen mitochondria lacking cristae as the main ultrastructural defect and potential cause of the disease. Patient analysis confirmed this structural hallmark. In addition, DNM2 reduction with antisense oligonucleotides after disease onset efficiently reverted locomotor and force defects after only 3 weeks of treatment. Most histological defects including mitochondria alteration were partially or fully rescued. Overall, this study highlights an efficient approach to revert the severe form of dynamin-related centronuclear myopathy. These data also reveal that the dynamin conformational switch is key for muscle function and should be targeted for future therapeutic developments.
经典的动力蛋白是调节膜和细胞骨架动态的大型 GTPases，它们与从神经肌肉疾病到脑病和癌症等不同的病理状况有关。显性动力蛋白 2（DNM2）突变导致轻度成人发病或严重常染色体显性中轴性肌病（ADCNM）。我们的目标是更好地了解严重 ADCNM 的发病机制并测试一种潜在的治疗方法。在这里，我们创建了携带常见 S619L 突变的 Dnm2SL/+ 小鼠品系，该突变存在于严重 ADCNM 患者中，并损害了调节动力蛋白自组装和膜重塑的构象开关。Dnm2SL/+ 小鼠忠实地再现了严重 ADCNM 的特征，表现为早期肌肉功能和力量受损，以及肌纤维萎缩。它揭示了肿胀的线粒体缺乏嵴，这是主要的超微结构缺陷和疾病的潜在原因。患者分析证实了这一结构特征。此外，疾病发作后用反义寡核苷酸降低 DNM2，仅治疗 3 周后，就有效地逆转了运动和力量缺陷。大多数组织学缺陷，包括线粒体改变，部分或完全得到了挽救。总体而言，这项研究强调了一种有效逆转与动力蛋白相关的中轴性肌病严重形式的方法。这些数据还表明，动力蛋白构象开关是肌肉功能的关键，应该成为未来治疗发展的目标。
