ArticleProceedings of the National Academy of Sciences of the United States of America2021
The N terminus of α-synuclein dictates fibril formation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed.
- O-GlcNAcylation: A molecular switch linking brain health to neurodegeneration.Neural regeneration research · 2026Article
- Probing the Energy Landscape of α-Synuclein Amyloid Fibril Formation by Systematic K-to-Q Mutagenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- In Vitro-Prepared A30P Alpha-Synuclein Fibrils Adopt the Conserved and Disease-Relevant Greek Key Fold.The journal of physical chemistry. B · 2026Article
- Differences in α-synuclein conformational states in physiologically relevant pH/NaThe Analyst · 2026Article
- Article
- Water Accelerates in the Hydration Shell of the N- and C-Terminal Domains of α-Synuclein in the Presence of NaCl.The journal of physical chemistry. B · 2026Article
- When Proteins Go MAD-Misfolded, Amplified, Detected: Advances in α-Synuclein Pathophysiology and RT-QuIC Detection.Molecular neurobiology · 2026Review
- Hidden faces of alpha-synuclein: Cryo-EM revelation of fibril polymorphs driven by disease, mutations, and PTMs.BBA advances · 2026Review
- Lipid-packing defects are sufficient to modulate membrane insertion and the bound state of α-synuclein.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- MAS Cryoprobe Enhances Solid-State NMR Signals of α-Synuclein Fibrils.bioRxiv : the preprint server for biology · 2025Article
- Surface wetting is a key determinant of α-synuclein condensate maturation.Communications chemistry · 2025Article
- Molecular Dynamics Study of α-Synuclein Domain Deletion Mutant Monomers.Biomolecules · 2025Article
- Mapping the Role of Monomer Conformation in the Amyloid Formation of α-Synuclein Splice Variants.Journal of the American Chemical Society · 2025Article
- Therapeutic Oligonucleotides for Neurodegenerative Diseases: Aptamer Strategies and Clay Nanoparticle-Based Delivery.Chemical record (New York, N.Y.) · 2025Review
- Article
- Alpha-synuclein fibril structures cluster into distinct classes.Biophysical journal · 2025Review
- Article
- Conformational Switch in the Alpha-Synuclein C-Terminal Domain Directs Its Fibril Polymorphs.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Amyloid formation of alternatively spliced variants of α-synuclein.Protein science : a publication of the Protein Society · 2025Article
- Ligands for Protein Fibrils of Amyloid-β, α-Synuclein, and Tau.Chemical reviews · 2025Review
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5 authors.
Funding
Abstract
The generation of α-synuclein (α-syn) truncations from incomplete proteolysis plays a significant role in the pathogenesis of Parkinson's disease. It is well established that C-terminal truncations exhibit accelerated aggregation and serve as potent seeds in fibril propagation. In contrast, mechanistic understanding of N-terminal truncations remains ill defined. Previously, we found that disease-related C-terminal truncations resulted in increased fibrillar twist, accompanied by modest conformational changes in a more compact core, suggesting that the N-terminal region could be dictating fibril structure. Here, we examined three N-terminal truncations, in which deletions of 13-, 35-, and 40-residues in the N terminus modulated both aggregation kinetics and fibril morphologies. Cross-seeding experiments showed that out of the three variants, only ΔN13-α-syn (14‒140) fibrils were capable of accelerating full-length fibril formation, albeit slower than self-seeding. Interestingly, the reversed cross-seeding reactions with full-length seeds efficiently promoted all but ΔN40-α-syn (41-140). This behavior can be explained by the unique fibril structure that is adopted by 41-140 with two asymmetric protofilaments, which was determined by cryogenic electron microscopy. One protofilament resembles the previously characterized bent β-arch kernel, comprised of residues E46‒K96, whereas in the other protofilament, fewer residues (E61‒D98) are found, adopting an extended β-hairpin conformation that does not resemble other reported structures. An interfilament interface exists between residues K60‒F94 and Q62‒I88 with an intermolecular salt bridge between K80 and E83. Together, these results demonstrate a vital role for the N-terminal residues in α-syn fibril formation and structure, offering insights into the interplay of α-syn and its truncations.
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