Presynaptic degeneration in ALS mouse neuromuscular junctions and a targeted therapeutic approach

项目摘要/摘要： 肌萎缩侧索硬化症(ALS)是一种神经退行性疾病，导致 运动神经元的进行性退化和功能丧失，导致瘫痪。研究 提示早期神经肌肉接头(NMJ)的突触传递减少 当脊髓中的神经元胞体出现时，NMJ疾病的各个阶段发生去神经支配 保持完好无损。NMJ功能障碍先于运动神经元死亡的观察 这表明肌萎缩侧索硬化症是一种“垂死性”神经病。ALS的病因目前尚不清楚，也没有 肌萎缩侧索硬化症的有效治疗方法是改善神经肌肉传递，这将改善 通过增加神经肌肉力量来提高ALS患者的生活质量，并可能延长寿命。 因此，我的长期目标是找到一种新的干预方法来改善神经肌肉 通过减少肌萎缩侧索硬化症患者的后遗神经病而发挥作用。我们的策略是测试一种新的针对Cav2的 我们开发的电压门控钙通道门控修饰剂(GV-58)，一种 增强神经肌肉系统活性的药物干预。GV-58 之所以具有创新性，是因为它基于以前没有进行过ALS测试的目标，即， 加强突触传递，维持NMJ神经支配。在此，我们建议 SOD1G93A患者疾病进展不同阶段的神经肌肉无力特征 并检测GV-58急性给药和每日慢性给药对小鼠ALS模型的影响。 这是为了确定GV-58是否可以在延缓NMJ的发病或恢复方面发挥作用 以及这是否能提高SOD1G93A小鼠的存活率。

Project Summary/Abstract: Amyotrophic Lateral Sclerosis (ALS) in a neurodegenerative disease that results in the progressive deterioration and loss of function of the motor neurons leading to paralysis. Studies indicated that synaptic transmission at neuromuscular junctions (NMJs) is reduced in early stages of the disease NMJ denervation occurs while neuronal cell bodies in the spinal cord remain intact. This observation in which NMJ dysfunction precedes motor neuron death suggests ALS is a “dying-back” neuropathy. The etiology of ALS is currently unknown, and no effective treatment exists for ALS to improve neuromuscular transmission, which would improve quality of life for ALS patients by increasing neuromuscular strength and may prolong lifespan. Therefore, my long-term goal is to identify a new intervention method to improve neuromuscular function by reducing dying-back neuropathy in ALS. Our strategy is to test a novel Cav2-specific voltage-gated calcium channel gating modifier that we have developed (GV-58), a pharmacological intervention that enhances the activation of the neuromuscular system. GV-58 is innovative because it is based on a target that has not been tested previously for ALS, namely, strengthening synaptic transmission to maintain NMJ innervation. Here, we propose to characterize neuromuscular weakness at different stages of disease progression in SOD1G93A ALS model mice and test the effects of GV-58 both acutely and after daily chronic administration. This is to determine if GV-58 can play a role in delaying disease onset or in recovery of NMJ strength and whether that can lead to improved SOD1G93A mouse survival.