ArticleScientific reports2018
Tryptophan 32-mediated SOD1 aggregation is attenuated by pyrimidine-like compounds in living cells.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 50 citations in OpenAlex.
- Development of a targeted BioPROTAC degrader selective for misfolded SOD1.Nature communications · 2025Article
- The Ile35 Residue of the ALS-Associated Mutant SOD1 Plays a Crucial Role in the Intracellular Aggregation of the Molecule.Molecular neurobiology · 2025Article
- Discovery of Novel Inhibitors against ALS-Related SOD1(A4V) Aggregation through the Screening of a Chemical Library Using Differential Scanning Fluorimetry (DSF).Pharmaceuticals (Basel, Switzerland) · 2024Article
- High-content analysis of proteostasis capacity in cellular models of amyotrophic lateral sclerosis (ALS).Scientific reports · 2024Article
- Amyloidogenic regions in beta-strands II and III modulate the aggregation and toxicity of SOD1 in living cells.Open biology · 2024Article
- 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
- Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis.Medicinal research reviews · 2023Review
- P2X7 receptor activation mediates superoxide dismutase 1 (SOD1) release from murine NSC-34 motor neurons.Purinergic signalling · 2022Article
- Structural analysis of the overoxidized Cu/Zn-superoxide dismutase in ROS-induced ALS filament formation.Communications biology · 2022Article
- SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity.Scientific reports · 2022Article
- Flow cytometry allows rapid detection of protein aggregates in cellular and zebrafish models of spinocerebellar ataxia 3.Disease models & mechanisms · 2021Article
- Variation in the vulnerability of mice expressing human superoxide dismutase 1 to prion-like seeding: a study of the influence of primary amino acid sequence.Acta neuropathologica communications · 2021Article
- Article
- Formation and characterization of crosslinks, including Tyr-Trp species, on one electron oxidation of free Tyr and Trp residues by carbonate radical anion.RSC advances · 2020Article
- Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises.Frontiers in cellular neuroscience · 2020Article
- Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection.PloS one · 2020Article
- The role of hydration effects in 5-fluorouridine binding to SOD1: insight from a new 3D-RISM-KH based protocol for including structural water in docking simulations.Journal of computer-aided molecular design · 2019Article
- Strategies to promote the maturation of ALS-associated SOD1 mutants: small molecules return to the fold.Neural regeneration research · 2019Article
- Prion-Like Propagation of Protein Misfolding and Aggregation in Amyotrophic Lateral Sclerosis.Frontiers in molecular neuroscience · 2019Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Over 160 mutations in superoxide dismutase 1 (SOD1) are associated with familial amyotrophic lateral sclerosis (fALS), where the main pathological feature is deposition of SOD1 into proteinaceous cytoplasmic inclusions. We previously showed that the tryptophan residue at position 32 (W32) mediates the prion-like propagation of SOD1 misfolding in cells, and that a W32S substitution blocks this phenomenon. Here, we used in vitro protein assays to demonstrate that a W32S substitution in SOD1-fALS mutants significantly diminishes their propensity to aggregate whilst paradoxically decreasing protein stability. We also show SOD1-W32S to be resistant to seeded aggregation, despite its high abundance of unfolded protein. A cell-based aggregation assay demonstrates that W32S substitution significantly mitigates inclusion formation. Furthermore, this assay reveals that W32 in SOD1 is necessary for the formation of a competent seed for aggregation under these experimental conditions. Following the observed importance of W32 for aggregation, we established that treatment of living cells with the W32-interacting 5-Fluorouridine (5-FUrd), and its FDA approved analogue 5-Fluorouracil (5-FU), substantially attenuate inclusion formation similarly to W32S substitution. Altogether, we highlight W32 as a significant contributor to SOD1 aggregation, and propose that 5-FUrd and 5-FU present promising lead drug candidates for the treatment of SOD1-associated ALS.
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