ArticleProceedings of the National Academy of Sciences of the United States of America2016
Kinetic model of the aggregation of alpha-synuclein provides insights into prion-like spreading.
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 129 papers.
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Who cites it
129 citing papers in PubMed.
- Cellular and systemic modifiers of alpha-synuclein proteostasis.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- Seeing Invisible Oligomers: Rethinking α-Synuclein Pathology Through Proximity Ligation Assay.Movement disorders : official journal of the Movement Disorder Society · 2026Review
- A Systematic Comparison of Alpha-Synuclein Seed Amplification Assays for Increasing Reproducibility.Annals of clinical and translational neurology · 2026Review
- Quantitative Analysis of Amyloid Fibril Nucleation by Linking Folding and Nucleation Pathways Using a Robust Ultrasonic Assay.ACS omega · 2026Article
- Concentration-dependent mutational scanning probes the cellular folding landscape of α-synuclein in yeast.Protein science : a publication of the Protein Society · 2026Article
- Propagation of α-synuclein pathology: models, mechanisms and future goals.Molecular neurodegeneration advances · 2026Review
- Concentration-Dependent Mutational Scanning Probes the Cellular Folding Landscape of α-Synuclein in Yeast.bioRxiv : the preprint server for biology · 2025Article
- Article
- Multivalent interaction induces phase separation and formation of more toxic aggregates of α-syn in a yeast model of Parkinson's disease.Protein science : a publication of the Protein Society · 2025Article
- A mechanistic model of pure and lipidic α-synuclein aggregation for advancing Parkinson's therapies.Communications chemistry · 2025Article
- Mass-Spectrometry-Based GEE Footprinting Characterizes Kinetic Mechanisms and Sites of Conformational Change in Amyloid β 1-42 Aggregation.ACS chemical neuroscience · 2025Article
- Effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability.Scientific reports · 2025Article
- A high-fidelity microfluidic platform reveals retrograde propagation as the main mechanism of α-Synuclein spread in human neurons.NPJ Parkinson's disease · 2025Article
- The role of RNA in the nanoscale organization of α-synuclein phase separation.NAR molecular medicine · 2025Article
- Characterizing heterogeneity in amyloid formation processes.Current opinion in structural biology · 2024Review
- α-Synuclein oligomers form by secondary nucleation.Nature communications · 2024Article
- Aβ Oligomer Dissociation Is Catalyzed by Fibril Surfaces.ACS chemical neuroscience · 2024Article
- A topographical atlas of α-synuclein dosage and cell type-specific expression in adult mouse brain and peripheral organs.NPJ Parkinson's disease · 2024Article
- Genetic Algorithm for Automated Parameterization of Network Hamiltonian Models of Amyloid Fibril Formation.The journal of physical chemistry. B · 2024Article
- Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases.Molecular neurodegeneration · 2024Review
69 more citing papers are in PubMed but not listed here.
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13 authors.
Funding
Abstract
The protein alpha-synuclein (αS) self-assembles into small oligomeric species and subsequently into amyloid fibrils that accumulate and proliferate during the development of Parkinson's disease. However, the quantitative characterization of the aggregation and spreading of αS remains challenging to achieve. Previously, we identified a conformational conversion step leading from the initially formed oligomers to more compact oligomers preceding fibril formation. Here, by a combination of single-molecule fluorescence measurements and kinetic analysis, we find that the reaction in solution involves two unimolecular structural conversion steps, from the disordered to more compact oligomers and then to fibrils, which can elongate by further monomer addition. We have obtained individual rate constants for these key microscopic steps by applying a global kinetic analysis to both the decrease in the concentration of monomeric protein molecules and the increase in oligomer concentrations over a 0.5-140-µM range of αS. The resulting explicit kinetic model of αS aggregation has been used to quantitatively explore seeding the reaction by either the compact oligomers or fibrils. Our predictions reveal that, although fibrils are more effective at seeding than oligomers, very high numbers of seeds of either type, of the order of 10(4), are required to achieve efficient seeding and bypass the slow generation of aggregates through primary nucleation. Complementary cellular experiments demonstrated that two orders of magnitude lower numbers of oligomers were sufficient to generate high levels of reactive oxygen species, suggesting that effective templated seeding is likely to require both the presence of template aggregates and conditions of cellular stress.
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