Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 69978, Israel.
Cell Death Dis. 2019 Mar 1;10(3):210. doi: 10.1038/s41419-019-1451-2.
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting both the upper and lower motor neurons (MNs), with no effective treatment currently available. Early pathological events in ALS include perturbations in axonal transport (AT), formation of toxic protein aggregates and Neuromuscular Junction (NMJ) disruption, which all lead to axonal degeneration and motor neuron death. Pridopidine is a small molecule that has been clinically developed for Huntington disease. Here we tested the efficacy of pridopidine for ALS using in vitro and in vivo models. Pridopidine beneficially modulates AT deficits and diminishes NMJ disruption, as well as motor neuron death in SOD1 MNs and in neuromuscular co-cultures. Furthermore, we demonstrate that pridopidine activates the ERK pathway and mediates its beneficial effects through the sigma-1 receptor (S1R). Strikingly, in vivo evaluation of pridopidine in SOD1 mice reveals a profound reduction in mutant SOD1 aggregation in the spinal cord, and attenuation of NMJ disruption, as well as subsequent muscle wasting. Taken together, we demonstrate for the first time that pridopidine improves several cellular and histological hallmark pathologies of ALS through the S1R.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，影响上下运动神经元（MNs），目前尚无有效治疗方法。ALS 中的早期病理事件包括轴突运输（AT）的扰动、毒性蛋白聚集体的形成和神经肌肉接头（NMJ）的破坏，所有这些都会导致轴突退化和运动神经元死亡。普里多宾是一种已在临床上开发用于亨廷顿病的小分子。在这里，我们使用体外和体内模型测试了普里多宾对 ALS 的疗效。普里多宾有益地调节 AT 缺陷，减少 NMJ 破坏，并减少 SOD1 MNs 和神经肌肉共培养物中的运动神经元死亡。此外，我们证明普里多宾激活 ERK 途径，并通过 sigma-1 受体（S1R）介导其有益作用。值得注意的是，普里多宾在 SOD1 小鼠中的体内评估显示，脊髓中突变型 SOD1 聚集物的显著减少，以及 NMJ 破坏的衰减，以及随后的肌肉萎缩。总之，我们首次证明普里多宾通过 S1R 改善 ALS 的几种细胞和组织学标志性病理学。
