ArticleBiophysical journal2015
Arresting amyloid with coulomb's law: acetylation of ALS-linked SOD1 by aspirin impedes aggregation.
Article in Biophysical journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 51 citations in OpenAlex.
- Role of Thrombosis in Neurodegenerative Diseases: An Intricate Mechanism of Neurovascular Complications.Molecular neurobiology · 2025Review
- Post-Translational Variants of Major Proteins in Amyotrophic Lateral Sclerosis Provide New Insights into the Pathophysiology of the Disease.International journal of molecular sciences · 2024Review
- Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications.Translational neurodegeneration · 2024Review
- Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases.Cell & bioscience · 2024Review
- Site Identification by Ligand Competitive Saturation-Biologics Approach for Structure-Based Protein Charge Prediction.Molecular pharmaceutics · 2023Article
- Electrostatic interactions mediate the nucleation and growth of a bacterial functional amyloid.Frontiers in molecular biosciences · 2023Article
- Altered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord.Brain : a journal of neurology · 2022Article
- Clinical Applications of Aspirin as a Multi-potent Drug Beyond Cardiovascular Implications: A Proof of Concept for Anesthesiologists- A Narrative Review.Anesthesiology and pain medicine · 2021Review
- Regulation of Functional Protein Aggregation by Multiple Factors: Implications for the Amyloidogenic Behavior of the CAP Superfamily Proteins.International journal of molecular sciences · 2020Review
- Acetylation of AβACS chemical neuroscience · 2020Article
- Article
- 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
- Mechanisms of SOD1 regulation by post-translational modifications.Redox biology · 2019Review
- Experimental Mutations in Superoxide Dismutase 1 Provide Insight into Potential Mechanisms Involved in Aberrant Aggregation in Familial Amyotrophic Lateral Sclerosis.G3 (Bethesda, Md.) · 2019Article
- Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis.Frontiers in molecular neuroscience · 2019Review
- Structural Insights Into TDP-43 and Effects of Post-translational Modifications.Frontiers in molecular neuroscience · 2019Review
- Aspirin-Mediated Acetylation Protects Against Multiple Neurodegenerative Pathologies by Impeding Protein Aggregation.Antioxidants & redox signaling · 2017Article
- Lysine acylation in superoxide dismutase-1 electrostatically inhibits formation of fibrils with prion-like seeding.The Journal of biological chemistry · 2017Article
- Acylation of Superoxide Dismutase 1 (SOD1) at K122 Governs SOD1-Mediated Inhibition of Mitochondrial Respiration.Molecular and cellular biology · 2017Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although the magnitude of a protein's net charge (Z) can control its rate of self-assembly into amyloid, and its interactions with cellular membranes, the net charge of a protein is not viewed as a druggable parameter. This article demonstrates that aspirin (the quintessential acylating pharmacon) can inhibit the amyloidogenesis of superoxide dismutase (SOD1) by increasing the intrinsic net negative charge of the polypeptide, i.e., by acetylation (neutralization) of multiple lysines. The protective effects of acetylation were diminished (but not abolished) in 100 mM NaCl and were statistically significant: a total of 432 thioflavin-T amyloid assays were performed for all studied proteins. The acetylation of as few as three lysines by aspirin in A4V apo-SOD1-a variant that causes familial amyotrophic lateral sclerosis (ALS)-delayed amyloid nucleation by 38% and slowed amyloid propagation by twofold. Lysines in wild-type- and ALS-variant apo-SOD1 could also be peracetylated with aspirin after fibrillization, resulting in supercharged fibrils, with increases in formal net charge of ∼2 million units. Peracetylated SOD1 amyloid defibrillized at temperatures below unacetylated fibrils, and below the melting temperature of native Cu2,Zn2-SOD1 (e.g., fibril Tm = 84.49°C for acetylated D90A apo-SOD1 fibrils). Targeting the net charge of native or misfolded proteins with small molecules-analogous to how an enzyme's Km or Vmax are medicinally targeted-holds promise as a strategy in the design of therapies for diseases linked to protein self-assembly.
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