Benedetti Lorena, Ghilardi Anna, Rottoli Elsa, De Maglie Marcella, Prosperi Laura, Perego Carla, Baruscotti Mirko, Bucchi Annalisa, Del Giacco Luca, Francolini Maura
Department of Medical Biotechnology and Translational Medicine, University of Milan, Neuroscience Institute, National Research Council (CNR), Via Vanvitelli 32, 20139 Milano, Italy.
Department of BioSciences, University of Milan, Via Celoria 26, 20133 Milano, Italy.
Sci Rep. 2016 Apr 15;6:24515. doi: 10.1038/srep24515.
The pathogenic role of SOD1 mutations in amyotrophic lateral sclerosis (ALS) was investigated using a zebrafish disease model stably expressing the ALS-linked G93R mutation. In addition to the main pathological features of ALS shown by adult fish, we found remarkably precocious alterations in the development of motor nerve circuitry and embryo behavior, and suggest that these alterations are prompted by interneuron and motor neuron hyperexcitability triggered by anomalies in the persistent pacemaker sodium current INaP. The riluzole-induced modulation of INaP reduced spinal neuron excitability, reverted the behavioral phenotypes and improved the deficits in motor nerve circuitry development, thus shedding new light on the use of riluzole in the management of ALS. Our findings provide a valid phenotype-based tool for unbiased in vivo drug screening that can be used to develop new therapies.
利用稳定表达与肌萎缩侧索硬化症（ALS）相关的G93R突变的斑马鱼疾病模型，研究了超氧化物歧化酶1（SOD1）突变在ALS中的致病作用。除了成年鱼所表现出的ALS主要病理特征外，我们还发现运动神经回路发育和胚胎行为出现了明显早熟的改变，并表明这些改变是由持续性起搏器钠电流INaP异常引发的中间神经元和运动神经元过度兴奋所导致的。利鲁唑对INaP的调节降低了脊髓神经元的兴奋性，逆转了行为表型，并改善了运动神经回路发育的缺陷，从而为利鲁唑在ALS治疗中的应用提供了新的线索。我们的研究结果为基于表型的无偏体内药物筛选提供了一个有效的工具，可用于开发新的治疗方法。
