| Structural highlights
Disease
SODC_HUMAN Defects in SOD1 are the cause of amyotrophic lateral sclerosis type 1 (ALS1) [MIM:105400. ALS1 is a familial form of amyotrophic lateral sclerosis, a neurodegenerative disorder affecting upper and lower motor neurons and resulting in fatal paralysis. Sensory abnormalities are absent. Death usually occurs within 2 to 5 years. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of cases leading to familial forms.[1] [2] [3] [4] [5] [6] [7] [8] [:][9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45]
Function
SODC_HUMAN Destroys radicals which are normally produced within the cells and which are toxic to biological systems.
Publication Abstract from PubMed
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 beta-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.
Distinct amyloid fibril structures formed by ALS-causing SOD1 mutants G93A and D101N.,Zhang MY, Ma Y, Wang LQ, Xia W, Li XN, Zhao K, Chen J, Li D, Zou L, Wang Z, Liu C, Liang Y EMBO Rep. 2025 Oct;26(19):4820-4846. doi: 10.1038/s44319-025-00557-8. Epub 2025 , Aug 26. PMID:40859014[46]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Zhang MY, Ma Y, Wang LQ, Xia W, Li XN, Zhao K, Chen J, Li D, Zou L, Wang Z, Liu C, Liang Y. Distinct amyloid fibril structures formed by ALS-causing SOD1 mutants G93A and D101N. EMBO Rep. 2025 Oct;26(19):4820-4846. PMID:40859014 doi:10.1038/s44319-025-00557-8
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