ERC Team, NeuroMyoGene Insitute - Now PGNM, Inserm U1315, CNRS UMR5261, University of Lyon 1, Lyon, France.
Montpellier Ressources Imagerie, BioCampus, University of Montpellier, CNRS, INSERM, Montpellier, France.
EMBO Mol Med. 2023 Jul 10;15(7):e16267. doi: 10.15252/emmm.202216267. Epub 2023 May 5.
Giant axonal neuropathy (GAN) is a fatal neurodegenerative disorder for which there is currently no treatment. Affecting the nervous system, GAN starts in infancy with motor deficits that rapidly evolve toward total loss of ambulation. Using the gan zebrafish model that reproduces the loss of motility as seen in patients, we conducted the first pharmacological screening for the GAN pathology. Here, we established a multilevel pipeline to identify small molecules restoring both the physiological and the cellular deficits in GAN. We combined behavioral, in silico, and high-content imaging analyses to refine our Hits to five drugs restoring locomotion, axonal outgrowth, and stabilizing neuromuscular junctions in the gan zebrafish. The postsynaptic nature of the drug's cellular targets provides direct evidence for the pivotal role the neuromuscular junction holds in the restoration of motility. Our results identify the first drug candidates that can now be integrated in a repositioning approach to fasten therapy for the GAN disease. Moreover, we anticipate both our methodological development and the identified hits to be of benefit to other neuromuscular diseases.
巨轴索神经病（GAN）是一种致命的神经退行性疾病，目前尚无治疗方法。该病影响神经系统，在婴儿期开始出现运动缺陷，迅速发展为完全丧失活动能力。我们使用重现了患者运动障碍的 gan 斑马鱼模型，对 GAN 病理进行了首次药物筛选。在这里，我们建立了一个多层次的管道，以识别能够恢复 GAN 生理和细胞缺陷的小分子。我们结合了行为、计算和高内涵成像分析，将我们的命中结果缩小到五种能够恢复 gan 斑马鱼运动、轴突生长和稳定神经肌肉接头的药物。药物细胞靶点的突触后性质为神经肌肉接头在恢复运动能力方面的关键作用提供了直接证据。我们的研究结果确定了第一批候选药物，这些药物现在可以整合到重新定位的方法中，以加快 GAN 疾病的治疗。此外，我们预计我们的方法发展和确定的命中结果将对其他神经肌肉疾病有益。
