ArticleNature chemical biology2024
Direct observation of prion-like propagation of protein misfolding templated by pathogenic mutants.
Article in Nature chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Tracking Protein Misfolding and Oligomerization: A Temperature-Controlled Ion Mobility-Mass Spectrometry Approach.Analytical chemistry · 2026Article
- Article
- Scalable assay to identify inhibitors of prion-like propagation of protein misfolding as potential therapeutics for neurodegeneration.Protein science : a publication of the Protein Society · 2026Article
- Neuroaxonal Degeneration as a Converging Mechanism in Motor Neuron Diseases (MNDs): Molecular Insights into RNA Dysregulation and Emerging Therapeutic Targets.International journal of molecular sciences · 2025Review
- Different folding mechanisms in prion proteins from mammals with different disease susceptibility observed at the single-molecule level.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Inhibition of SOD1 trimerization is a novel drug target for ALS disease.Translational neurodegeneration · 2025Article
- Inhibition of tau neuronal internalization using anti-tau single domain antibodies.Nature communications · 2025Article
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
Many neurodegenerative diseases feature misfolded proteins that propagate via templated conversion of natively folded molecules. However, crucial questions about how such prion-like conversion occurs and what drives it remain unsolved, partly because technical challenges have prevented direct observation of conversion for any protein. We observed prion-like conversion in single molecules of superoxide dismutase-1 (SOD1), whose misfolding is linked to amyotrophic lateral sclerosis. Tethering pathogenic misfolded SOD1 mutants to wild-type molecules held in optical tweezers, we found that the mutants vastly increased misfolding of the wild-type molecule, inducing multiple misfolded isoforms. Crucially, the pattern of misfolding was the same in the mutant and converted wild-type domains and varied when the misfolded mutant was changed, reflecting the templating effect expected for prion-like conversion. Ensemble measurements showed decreased enzymatic activity in tethered heterodimers as conversion progressed, mirroring the single-molecule results. Antibodies sensitive to disease-specific epitopes bound to the converted protein, implying that conversion produced disease-relevant misfolded conformers.
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Registered trials
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