| 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
Fibrils and oligomers are the aggregated protein agents of neuronal dysfunction in ALS diseases. Whereas we now know much about fibril architecture, atomic structures of disease-related oligomers have eluded determination. Here, we determine the corkscrew-like structure of a cytotoxic segment of superoxide dismutase 1 (SOD1) in its oligomeric state. Mutations that prevent formation of this structure eliminate cytotoxicity of the segment in isolation as well as cytotoxicity of the ALS-linked mutants of SOD1 in primary motor neurons and in a Danio rerio (zebrafish) model of ALS. Cytotoxicity assays suggest that toxicity is a property of soluble oligomers, and not large insoluble aggregates. Our work adds to evidence that the toxic oligomeric entities in protein aggregation diseases contain antiparallel, out-of-register beta-sheet structures and identifies a target for structure-based therapeutics in ALS.
Atomic structure of a toxic, oligomeric segment of SOD1 linked to amyotrophic lateral sclerosis (ALS).,Sangwan S, Zhao A, Adams KL, Jayson CK, Sawaya MR, Guenther EL, Pan AC, Ngo J, Moore DM, Soriaga AB, Do TD, Goldschmidt L, Nelson R, Bowers MT, Koehler CM, Shaw DE, Novitch BG, Eisenberg DS Proc Natl Acad Sci U S A. 2017 Aug 15;114(33):8770-8775. doi:, 10.1073/pnas.1705091114. Epub 2017 Jul 31. PMID:28760994[46]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Sangwan S, Zhao A, Adams KL, Jayson CK, Sawaya MR, Guenther EL, Pan AC, Ngo J, Moore DM, Soriaga AB, Do TD, Goldschmidt L, Nelson R, Bowers MT, Koehler CM, Shaw DE, Novitch BG, Eisenberg DS. Atomic structure of a toxic, oligomeric segment of SOD1 linked to amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A. 2017 Aug 15;114(33):8770-8775. doi:, 10.1073/pnas.1705091114. Epub 2017 Jul 31. PMID:28760994 doi:http://dx.doi.org/10.1073/pnas.1705091114
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