ArticleProceedings of the National Academy of Sciences of the United States of America2016
Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 127 citations in OpenAlex.
- Assessment of Aggregation- and Condensation-Prone Regions of Proteins Involved in Neurodegenerative, Neurological and Mental-State Diseases.Biomolecules · 2026Article
- Targeting soluble misfolded oligomers in anti-amyloid research.Nature reviews. Chemistry · 2026Review
- Nose-to-brain delivery of a SOD1-stabilizing small molecule ameliorates pathology in an ALS mouse model.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers.Neurobiology of disease · 2026Article
- N-terminal acetylation of superoxide dismutase 1 accelerates amyloid formation without general destabilization of the apo state.Protein science : a publication of the Protein Society · 2025Article
- Trimeric superoxide dismutase 1 antibody as a universal biomarker for ALS.Research square · 2025Article
- Inhibition of SOD1 trimerization is a novel drug target for ALS disease.Translational neurodegeneration · 2025Article
- A structure-guided antibody detects SOD1 oligomers in diverse ALS genotypes.bioRxiv : the preprint server for biology · 2025Article
- Inhibition of Salt-Inducible Kinase 2 Protects Motor Neurons From Degeneration in ALS by Activating Autophagic Flux and Enhancing mTORC1 Activity.CNS neuroscience & therapeutics · 2025Article
- Biophysical and spectroscopical insights into structural modulation of species in the aggregation pathway of superoxide dismutase 1.Communications chemistry · 2025Article
- Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells.Structure (London, England : 1993) · 2024Article
- Rutin Ameliorates ALS Pathology by Reducing SOD1 Aggregation and Neuroinflammation in an SOD1-G93A Mouse Model.International journal of molecular sciences · 2024Article
- High-content analysis of proteostasis capacity in cellular models of amyotrophic lateral sclerosis (ALS).Scientific reports · 2024Article
- Review
- The Role of Protein S-Nitrosylation in Mitochondrial Quality Control in Central Nervous System Diseases.Aging and disease · 2024Review
- Protein aggregation and therapeutic strategies in SOD1- and TDP-43- linked ALS.Frontiers in molecular biosciences · 2024Review
- Structural insights into the modulation Of SOD1 aggregation By a fungal metabolite Phialomustin-B: Therapeutic potential in ALS.PloS one · 2024Article
- Exosomal TAR DNA binding protein 43 profile in canine model of amyotrophic lateral sclerosis: a preliminary study in developing blood-based biomarker for neurodegenerative diseases.Annals of medicine · 2023Article
- Coordination chemistry of mitochondrial copper metalloenzymes: exploring implications for copper dyshomeostasis in cell death.BMB reports · 2023Review
- Big versus small: The impact of aggregate size in disease.Protein science : a publication of the Protein Society · 2023Review
5 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Since the linking of mutations in the Cu,Zn superoxide dismutase gene (sod1) to amyotrophic lateral sclerosis (ALS) in 1993, researchers have sought the connection between SOD1 and motor neuron death. Disease-linked mutations tend to destabilize the native dimeric structure of SOD1, and plaques containing misfolded and aggregated SOD1 have been found in the motor neurons of patients with ALS. Despite advances in understanding of ALS disease progression and SOD1 folding and stability, cytotoxic species and mechanisms remain unknown, greatly impeding the search for and design of therapeutic interventions. Here, we definitively link cytotoxicity associated with SOD1 aggregation in ALS to a nonnative trimeric SOD1 species. We develop methodology for the incorporation of low-resolution experimental data into simulations toward the structural modeling of metastable, multidomain aggregation intermediates. We apply this methodology to derive the structure of a SOD1 trimer, which we validate in vitro and in hybridized motor neurons. We show that SOD1 mutants designed to promote trimerization increase cell death. Further, we demonstrate that the cytotoxicity of the designed mutants correlates with trimer stability, providing a direct link between the presence of misfolded oligomers and neuron death. Identification of cytotoxic species is the first and critical step in elucidating the molecular etiology of ALS, and the ability to manipulate formation of these species will provide an avenue for the development of future therapeutic strategies.
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