ArticleThe Journal of biological chemistry2014
Identification of a misfolded region in superoxide dismutase 1 that is exposed in amyotrophic lateral sclerosis.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 35 citations in OpenAlex.
- Reliable repurposing of the antibody interactome inside the cell.Nature communications · 2026Article
- Oxidative denaturation of Cu/Zn-superoxide dismutase associated with neurodegenerative diseases.Protein science : a publication of the Protein Society · 2025Article
- Disulfide-mediated oligomerization of mutant Cu/Zn-superoxide dismutase associated with canine degenerative myelopathy.Protein science : a publication of the Protein Society · 2024Article
- Direct observation of prion-like propagation of protein misfolding templated by pathogenic mutants.Nature chemical biology · 2024Article
- Seeding activity of human superoxide dismutase 1 aggregates in familial and sporadic amyotrophic lateral sclerosis postmortem neural tissues by real-time quaking-induced conversion.Acta neuropathologica · 2024Article
- Anti-SOD1 Nanobodies That Stabilize Misfolded SOD1 Proteins Also Promote Neurite Outgrowth in Mutant SOD1 Human Neurons.International journal of molecular sciences · 2022Article
- Pridopidine modifies disease phenotype in a SOD1 mouse model of amyotrophic lateral sclerosis.The European journal of neuroscience · 2022Article
- A Metal-Free, Disulfide Oxidized Form of Superoxide Dismutase 1 as a Primary Misfolded Species with Prion-Like Properties in the Extracellular Environments Surrounding Motor Neuron-Like Cells.International journal of molecular sciences · 2021Article
- Trifluoroethanol Partially Unfolds G93A SOD1 Leading to Protein Aggregation: A Study by Native Mass Spectrometry and FPOP Protein Footprinting.Biochemistry · 2020Article
- Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection.PloS one · 2020Article
- Wild-type Cu/Zn-superoxide dismutase is misfolded in cerebrospinal fluid of sporadic amyotrophic lateral sclerosis.Molecular neurodegeneration · 2019Article
- Proteomics Approaches for Biomarker and Drug Target Discovery in ALS and FTD.Frontiers in neuroscience · 2019Review
- Structural Properties and Interaction Partners of Familial ALS-Associated SOD1 Mutants.Frontiers in neurology · 2019Review
- Article
- Partially native intermediates mediate misfolding of SOD1 in single-molecule folding trajectories.Nature communications · 2017Article
- Parsing disease-relevant protein modifications from epiphenomena: perspective on the structural basis of SOD1-mediated ALS.Journal of mass spectrometry : JMS · 2017Article
- Immunochemical characterization on pathological oligomers of mutant Cu/Zn-superoxide dismutase in amyotrophic lateral sclerosis.Molecular neurodegeneration · 2017Article
- A Phosphomimetic Mutation Stabilizes SOD1 and Rescues Cell Viability in the Context of an ALS-Associated Mutation.Structure (London, England : 1993) · 2016Article
- Mutant SOD1 protein increases Nav1.3 channel excitability.Journal of biological physics · 2016Article
- ALS-linked misfolded SOD1 species have divergent impacts on mitochondria.Acta neuropathologica communications · 2016Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations and aberrant post-translational modifications within Cu,Zn-superoxide dismutase (SOD1) cause this otherwise protective enzyme to misfold, leading to amyotrophic lateral sclerosis (ALS). The C4F6 antibody selectively binds misfolded SOD1 in spinal cord tissues from postmortem human ALS cases, as well as from an ALS-SOD1 mouse model, suggesting that the C4F6 epitope reports on a pathogenic conformation that is common to misfolded SOD1 variants. To date, the residues and structural elements that comprise this epitope have not been elucidated. Using a chemical cross-linking and mass spectrometry approach, we identified the C4F6 epitope within several ALS-linked SOD1 variants, as well as an oxidized form of WT SOD1, supporting the notion that a similar misfolded conformation is shared among pathological SOD1 proteins. Exposure of the C4F6 epitope was modulated by the SOD1 electrostatic (loop VII) and zinc binding (loop IV) loops and correlated with SOD1-induced toxicity in a primary microglia activation assay. Site-directed mutagenesis revealed Asp(92) and Asp(96) as key residues within the C4F6 epitope required for the SOD1-C4F6 binding interaction. We propose that stabilizing the functional loops within SOD1 and/or obscuring the C4F6 epitope are viable therapeutic strategies for treating SOD1-mediated ALS.
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