ArticleJournal of the American Chemical Society2024
A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion.
Article in Journal of the American Chemical Society, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- α-Synuclein Forms Distinct Micelle-Like Assemblies at Low Ionic Strengths.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson's disease.Nature communications · 2026Article
- Cross-link Between CircRNAs and Neuroinflammation in Parkinson's Disease.Molecular neurobiology · 2026Review
- Article
- In silico peptide self-assembly reveals the importance of N-terminal motifs and the inhibition mechanism of the mutation L38M in α-synuclein fibrillation.Protein science : a publication of the Protein Society · 2026Article
- Article
- When Proteins Go MAD-Misfolded, Amplified, Detected: Advances in α-Synuclein Pathophysiology and RT-QuIC Detection.Molecular neurobiology · 2026Review
- Surface wetting is a key determinant of α-synuclein condensate maturation.Communications chemistry · 2025Article
- Mapping the Role of Monomer Conformation in the Amyloid Formation of α-Synuclein Splice Variants.Journal of the American Chemical Society · 2025Article
- ZnJournal of the American Chemical Society · 2025Article
- Article
- Structural Context Modulates the Conformational Ensemble of the Intrinsically Disordered Amino Terminus of α-Synuclein.Journal of the American Chemical Society · 2025Article
- HRaDeX: R Package and Web Server for Computing High-Resolution Deuterium Uptake Rates for HDX-MS Data.Journal of proteome research · 2025Article
- Molecular Rotors Detect the Formation and Conversion of α-Synuclein Oligomers.ACS applied materials & interfaces · 2025Article
- The role of amphipathic and cationic helical peptides in Parkinson's disease.Protein science : a publication of the Protein Society · 2025Review
- Structures of Oligomeric States of Tau Protein, Amyloid-β, α-Synuclein and Prion Protein Implicated in Alzheimer's Disease, Parkinson's Disease and Prionopathies.International journal of molecular sciences · 2024Review
- The small molecule ZPD-2 inhibits the aggregation and seeded polymerisation of C-terminally truncated α-Synuclein.The FEBS journal · 2024Article
- Characterizing heterogeneity in amyloid formation processes.Current opinion in structural biology · 2024Review
- A Potent Sybody Selectively Inhibits α-Synuclein Amyloid Formation by Binding to the P1 Region.Journal of medicinal chemistry · 2024Article
Corrections and comments
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Authors and funding
18 authors.
Funding
Abstract
Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36-61) that populates a distinct conformation in the mono- and oligomeric states. This α-synuclein region plays a pivotal role in oligomer-to-fibril conversion as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early onset Parkinson's disease, causes a conformational fluctuation in this region, leading to delayed oligomer-to-fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in α-synuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.