Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
AcuraStem Incorporated, Monrovia, CA 91016, USA.
Cell Stem Cell. 2023 Feb 2;30(2):171-187.e14. doi: 10.1016/j.stem.2023.01.005.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by many diverse genetic etiologies. Although therapeutics that specifically target causal mutations may rescue individual types of ALS, such approaches cannot treat most patients since they have unknown genetic etiology. Thus, there is a critical need for therapeutic strategies that rescue multiple forms of ALS. Here, we combine phenotypic chemical screening on a diverse cohort of ALS patient-derived neurons with bioinformatic analysis of large chemical and genetic perturbational datasets to identify broadly effective genetic targets for ALS. We show that suppressing the gene-encoding, spliceosome-associated factor SYF2 alleviates TDP-43 aggregation and mislocalization, improves TDP-43 activity, and rescues C9ORF72 and causes sporadic ALS neuron survival. Moreover, Syf2 suppression ameliorates neurodegeneration, neuromuscular junction loss, and motor dysfunction in TDP-43 mice. Thus, suppression of spliceosome-associated factors such as SYF2 may be a broadly effective therapeutic approach for ALS.
肌萎缩侧索硬化症（ALS）是一种由多种不同遗传病因引起的致命神经退行性疾病。虽然针对病因突变的特定治疗方法可能会挽救特定类型的 ALS，但由于大多数患者的遗传病因未知，这些方法无法治疗大多数患者。因此，急需针对多种 ALS 形式的治疗策略。在这里，我们结合了对不同队列的 ALS 患者来源神经元的表型化学筛选，以及对大型化学和遗传扰动数据集的生物信息学分析，以确定 ALS 的广泛有效的遗传靶标。我们发现，抑制编码剪接体相关因子 SYF2 的基因可以减轻 TDP-43 的聚集和定位错误，提高 TDP-43 的活性，并挽救 C9ORF72 并导致散发性 ALS 神经元存活。此外，SYF2 的抑制可改善 TDP-43 小鼠的神经退行性变、运动神经元-运动终板丧失和运动功能障碍。因此，抑制剪接体相关因子如 SYF2 可能是一种针对 ALS 的广泛有效的治疗方法。
