ArticleRedox biology2019
Biasing the native α-synuclein conformational ensemble towards compact states abolishes aggregation and neurotoxicity.
Article in Redox biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Nanopipettes Enable Native Mass Spectrometry Studies of the Intrinsically Disordered Protein α-Synuclein in Biochemical Buffers.Analytical chemistry · 2026Article
- Machine learning-assisted screening of small-molecule drugs for suppressing protein aggregation and ROS generation based on ECL and CV dual-mode signals amplified by DNA.Chemical science · 2026Article
- Disulfide engineering reveals unexpected pro- and anti-aggregation conformers of human α-synuclein.bioRxiv : the preprint server for biology · 2026Article
- Is synuclein aggregation a derived or ancestral trait? Ancestral sequence reconstruction uncovers stepwise evolution of synuclein aggregation.bioRxiv : the preprint server for biology · 2025Article
- Local Ionic Conditions Modulate the Aggregation Propensity and Influence the Structural Polymorphism of α-Synuclein.Journal of the American Chemical Society · 2025Article
- Salt-Induced Membrane-Bound Conformation of the NAC Domain of α-Synuclein Leads to Structural Polymorphism of Amyloid Fibrils.Biomolecules · 2025Article
- Taking Charge: Metal Ions Accelerate Amyloid Aggregation in Sequence Variants of α-Synuclein.Journal of the American Society for Mass Spectrometry · 2023Article
- Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons.Biomedicines · 2022Review
- C-terminal truncation modulates α-Synuclein's cytotoxicity and aggregation by promoting the interactions with membrane and chaperone.Communications biology · 2022Article
- Potent inhibitors of toxic alpha-synuclein identified via cellular time-resolved FRET biosensors.NPJ Parkinson's disease · 2021Article
- Identification of Two Novel Peptides That Inhibit α-Synuclein Toxicity and Aggregation.Frontiers in molecular neuroscience · 2021Article
- The Janus face of N-terminal lysines in α-synuclein.Neural regeneration research · 2020Article
- Direct Identification of Amyloid Peptide Fragments in Human α-Synuclein Based on Consecutive Hydrophobic Amino Acids.ACS omega · 2020Article
- Inhibition of α-Synuclein Aggregation and Mature Fibril Disassembling With a Minimalistic Compound, ZPDm.Frontiers in bioengineering and biotechnology · 2020Article
- Tuning Functional Amyloid Formation Through Disulfide Engineering.Frontiers in microbiology · 2020Article
- Inducing α-synuclein compaction: a new strategy for inhibiting α-synuclein aggregation?Neural regeneration research · 2019Article
- ZPD-2, a Small Compound That Inhibits α-Synuclein Amyloid Aggregation and Its Seeded Polymerization.Frontiers in molecular neuroscience · 2019Article
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The aggregation of α-synuclein (α-syn) into amyloid fibrils is a major pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. The mechanisms underlying the structural transition of soluble and innocuous α-syn to aggregated neurotoxic forms remains largely unknown. The disordered nature of α-syn has hampered the use of structure-based protein engineering approaches to elucidate the molecular determinants of this transition. The recent 3D structure of a pathogenic α-syn fibril provides a template for this kind of studies. The structure supports the NAC domain being a critical element in fibril formation, since it constitutes the core of the fibril, delineating a Greek-key motif. Here, we stapled the ends of this motif with a designed disulfide bond and evaluated its impact on the conformation, aggregation and toxicity of α-syn in different environments. The new covalent link biases the native structural ensemble of α-syn toward compact conformations, reducing the population of fully unfolded species. This conformational bias results in a strongly reduced fibril formation propensity both in the absence and in the presence of lipids and impedes the formation of neurotoxic oligomers. Our study does not support the Greek-key motif being already imprinted in early α-syn assemblies, discarding it as a druggable interface to prevent the initiation of fibrillation. In contrast, it suggests the stabilization of native, compact ensembles as a potential therapeutic strategy to avoid the formation of toxic species and to target the early stages of PD.
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