Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France.
Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France
Dis Model Mech. 2018 Jul 20;11(7):dmm033811. doi: 10.1242/dmm.033811.
Friedreich's ataxia (FA) is caused by reduced levels of frataxin, a highly conserved mitochondrial protein. There is currently no effective treatment for this disease, which is characterized by progressive neurodegeneration and cardiomyopathy, the latter being the most common cause of death in patients. We previously developed a cardiac model of FA, in which the fly frataxin is inactivated specifically in the heart, leading to heart dilatation and impaired systolic function. Methylene Blue (MB) was highly efficient to prevent these cardiac dysfunctions. Here, we used this model to screen the Prestwick Chemical Library, comprising 1280 compounds. Eleven drugs significantly reduced the cardiac dilatation, some of which may possibly lead to therapeutic applications in the future. The one with the strongest protective effects was paclitaxel, a microtubule-stabilizing drug. In parallel, we characterized the histological defects induced by frataxin deficiency in cardiomyocytes and observed strong sarcomere alterations with loss of striation of actin fibers, along with full disruption of the microtubule network. Paclitaxel and MB both improved these structural defects. Therefore, we propose that frataxin inactivation induces cardiac dysfunction through impaired sarcomere assembly or renewal due to microtubule destabilization, without excluding additional mechanisms. This study is the first drug screening of this extent performed on a model of cardiac disease. Thus, it also brings the proof of concept that cardiac functional imaging in adult flies is usable for medium-scale pharmacological screening, with potent identification of cardioprotective drugs in various contexts of cardiac diseases.
弗里德赖希共济失调（FA）是由高度保守的线粒体蛋白 frataxin 水平降低引起的。目前，这种疾病还没有有效的治疗方法，其特征是进行性神经退行性变和心肌病，后者是患者死亡的最常见原因。我们之前开发了一种 FA 的心脏模型，其中果蝇 frataxin 特异性地在心脏中失活，导致心脏扩张和收缩功能受损。亚甲蓝（MB）非常有效地预防了这些心脏功能障碍。在这里，我们使用这个模型筛选了包含 1280 种化合物的 Prestwick 化学库。有 11 种药物显著降低了心脏扩张，其中一些药物将来可能具有治疗应用的潜力。保护作用最强的是紫杉醇，一种微管稳定剂。同时，我们还描述了 frataxin 缺乏导致心肌细胞中的组织学缺陷，并观察到肌节强烈改变，肌动蛋白纤维的条纹消失，微管网络完全破坏。紫杉醇和 MB 都改善了这些结构缺陷。因此，我们提出 frataxin 失活通过微管稳定性破坏导致肌节组装或更新受损，从而引起心脏功能障碍，不排除其他机制。这项研究是首次对心脏疾病模型进行如此程度的药物筛选。因此，它还提供了一个概念验证，即成年果蝇的心脏功能成像可用于中等规模的药理学筛选，在各种心脏疾病的情况下都能有效地鉴定出心脏保护药物。
