Zhang Mu-Ya, Ma Yeyang, Wang Li-Qiang, Xia Wencheng, Li Xiang-Ning, Zhao Kun, Chen Jie, Li Dan, Zou Liangyu, Wang Zhengzhi, Liu Cong, Liang Yi
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, 430072, Wuhan, China.
Interdisciplinary Research Center on Biology and Chemistry, State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201210, Shanghai, China.
EMBO Rep. 2025 Aug 26. doi: 10.1038/s44319-025-00557-8.
Two hundred eight genetic mutations in SOD1 have been linked to amyotrophic lateral sclerosis (ALS). Of these, the G93A and D101N variants maintain much of their physiological function, closely resembling that of wild-type SOD1, and the SOD1-G93A transgenic mouse is the most extensively used mouse line in the study of ALS. In this study, we report two cryo-EM structures of amyloid fibrils formed by G93A and D101N mutants of SOD1 protein. These mutations give rise to amyloid fibrils with distinct structures compared to native SOD1 fibrils. The fibril core displays a serpentine configuration featuring four β-strands, held together by two hydrophobic cavities and a salt bridge between Arg143 and Asp96 in the G93A fibril, and by a hydrophobic cavity and a salt bridge between Arg143 and Asp132 in the D101N fibril, demonstrating unique structural features for each mutant. Moreover, our results show that G93A fibrils are significantly more toxic than those formed by D101N, which do not show a marked increase in toxicity compared to wild-type SOD1 fibrils. This study sheds light on the structural mechanisms through which SOD1 mutants aggregate and induce cytotoxicity in ALS.
超氧化物歧化酶1（SOD1）中的208种基因突变已与肌萎缩侧索硬化症（ALS）相关联。其中，G93A和D101N变体保留了大部分生理功能，与野生型SOD1非常相似，并且SOD1 - G93A转基因小鼠是ALS研究中使用最广泛的小鼠品系。在本研究中，我们报告了由SOD1蛋白的G93A和D101N突变体形成的淀粉样纤维的两种冷冻电镜结构。与天然SOD1纤维相比，这些突变产生了具有不同结构的淀粉样纤维。纤维核心呈现出一种蛇形构型，具有四条β链，在G93A纤维中由两个疏水腔以及Arg143和Asp96之间的盐桥维系在一起，而在D101N纤维中由一个疏水腔以及Arg143和Asp132之间的盐桥维系在一起，这表明每个突变体都有独特的结构特征。此外，我们的结果表明，G93A纤维的毒性明显高于D101N形成的纤维，与野生型SOD1纤维相比，D101N形成的纤维毒性没有显著增加。这项研究揭示了SOD1突变体在ALS中聚集并诱导细胞毒性的结构机制。
