美国南加州大学Justin K. Ichida研究团队的一项最新研究发现抑制SYF2减弱不同形式肌萎缩侧索硬化症（ALS）模型的神经退行性变。这一研究成果发表在2023年2月2日出版的国际学术期刊《细胞—干细胞》上。

研究人员对ALS患者来源神经元不同队列的表型筛选与大型化学和遗传扰动数据集的生物信息学分析相结合，以确定靶向ALS广泛有效的遗传靶点。研究表明，抑制基因编码、剪接体相关因子SYF2减轻了TDP-43的聚集和错误定位，改善TDP-43活性，并挽救了由C9ORF72导致的散发型ALS神经元的存活。

此外，抑制Syf2可改善TDP-43小鼠的神经变性、神经肌肉接头丧失和运动功能障碍。因此，抑制剪接体相关因子（如SYF2）可能是治疗ALS的一种广泛有效的方法。

研究人员表示，ALS是一种致命的神经退行性疾病，由许多不同的遗传病因导致。尽管专门针对因果突变的治疗方法可以挽救个别类型的ALS，但这种方法不能治疗大多数患者，因为ALS具有未知的遗传病因。因此，迫切需要适用于多种形式ALS的治疗策略。

附：英文原文

Title: SYF2 suppression mitigates neurodegeneration in models of diverse forms of ALS

Author: Gabriel R. Linares, Yichen Li, Wen-Hsuan Chang, Jasper Rubin-Sigler, Stacee Mendonca, Sarah Hong, Yunsun Eoh, Wenxuan Guo, Yi-Hsuan Huang, Jonathan Chang, Sharon Tu, Nomongo Dorjsuren, Manuel Santana, Shu-Ting Hung, Johnny Yu, Joscany Perez, Michael Chickering, Tze-Yuan Cheng, Chi-Chou Huang, Shih-Jong James Lee, Hao-Jen Deng, Kieu-Tram Bach, Kamden Gray, Vishvak Subramanyam, Jeffrey Rosenfeld, Samuel V. Alworth, Hani Goodarzi, Justin K. Ichida

Issue&Volume: 2023/02/02

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused bymany diverse genetic etiologies. Although therapeutics that specifically target causalmutations may rescue individual types of ALS, such approaches cannot treat most patientssince they have unknown genetic etiology. Thus, there is a critical need for therapeuticstrategies that rescue multiple forms of ALS. Here, we combine phenotypic chemicalscreening on a diverse cohort of ALS patient-derived neurons with bioinformatic analysisof large chemical and genetic perturbational datasets to identify broadly effectivegenetic targets for ALS. We show that suppressing the gene-encoding, spliceosome-associatedfactor 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 motordysfunction in TDP-43 mice. Thus, suppression of spliceosome-associated factors suchas SYF2 may be a broadly effective therapeutic approach for ALS.

DOI: 10.1016/j.stem.2023.01.005

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00005-X