Distinct amyloid fibril structures formed by ALS-causing SOD1 mutants G93A and D101N
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.
Authors
- Kun Zhao (ORCID: https://orcid.org/0000-0002-6524-8715)
- Yi Liang (ORCID: https://orcid.org/0000-0002-7349-8300)
- Yeyang Ma (ORCID: https://orcid.org/0000-0002-7498-110X)
- Mu-Ya Zhang
- Zhengzhi Wang (ORCID: https://orcid.org/0000-0001-5699-8330)
- Jie Chen (ORCID: https://orcid.org/0000-0002-2980-6601)
- Wencheng Xia (ORCID: https://orcid.org/0000-0002-2100-7055)
- Xiangning Li (ORCID: https://orcid.org/0000-0002-3747-2824)
- Liangyu Zou (ORCID: https://orcid.org/0000-0001-8066-8892)
- Cong Liu (ORCID: https://orcid.org/0000-0003-3425-6672)
- Dan Li (ORCID: https://orcid.org/0000-0003-3461-5751)
- Liqiang Wang (ORCID: https://orcid.org/0000-0002-5377-3168)
Institutions
- Shanghai Academy of Social Sciences (CN)
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- Southern University of Science and Technology (CN)
- Jianghan University (CN)
- Wuhan University (CN)
- Shanghai Advanced Research Institute (CN)
- Shanghai Institute of Organic Chemistry (CN)
- Ministry of Education (KR)
- Southern Medical University Shenzhen Hospital (CN)
- Shenzhen Second People's Hospital (CN)
- University of Chinese Academy of Sciences (CN)
- Hubei University (CN)
Publication Details
- Journal
- EMBO Reports
- Published
- 2025-08-26
- DOI
- https://doi.org/10.1038/s44319-025-00557-8
- Citations
- 3
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 4.17
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- National Science and Technology Major Project
- National Key Research and Development Program of China
- Science and Technology Planning Project of Shenzhen Municipality