ArticleProceedings of the National Academy of Sciences of the United States of America2020
The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 104 papers.
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104 citing papers in PubMed, 174 citations in OpenAlex.
- Probing the Energy Landscape of α-Synuclein Amyloid Fibril Formation by Systematic K-to-Q Mutagenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Genetics of α-Synuclein: The Prime Pathological Player of Parkinson's Disease.Neurotoxicity research · 2026Review
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- In Vitro-Prepared A30P Alpha-Synuclein Fibrils Adopt the Conserved and Disease-Relevant Greek Key Fold.The journal of physical chemistry. B · 2026Article
- Amyloid exacerbates tau and alpha-synuclein pathologies, behavioral impairments, and neuroinflammation in a mixed dementia model.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Fragmentation-Induced Disassembly and Reaggregation of α-Synuclein Amyloid Fibrils.ACS chemical neuroscience · 2026Article
- Reconstitution of protein arginylation pathways in bacteria for robust identification and quantification.Communications biology · 2026Article
- Reverse-engineering amyloid strains with generative protein design.bioRxiv : the preprint server for biology · 2026Article
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- 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
- Molecular Dynamics Study of α-Synuclein Domain Deletion Mutant Monomers.Biomolecules · 2025Article
- Current Understanding of Protein Aggregation in Neurodegenerative Diseases.International journal of molecular sciences · 2025Review
- A comprehensive application of FiveFold for conformation ensemble-based protein structure prediction.Scientific reports · 2025Review
- Conformational Ensemble Dynamics of Intrinsically Disordered Full-Length α- and β-Synuclein Monomers.Journal of chemical information and modeling · 2025Article
- Alpha-synuclein fibril structures cluster into distinct classes.Biophysical journal · 2025Review
- 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
- The evolving role of solid state nuclear magnetic resonance methods in studies of amyloid fibrils.Current opinion in structural biology · 2025Review
- Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation.Nature communications · 2025Article
44 more citing papers are in PubMed but not listed here.
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9 authors at 3 institutions in 1 country.
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Abstract
Aggregation of α-synuclein is a defining molecular feature of Parkinson's disease, Lewy body dementia, and multiple systems atrophy. Hereditary mutations in α-synuclein are linked to both Parkinson's disease and Lewy body dementia; in particular, patients bearing the E46K disease mutation manifest a clinical picture of parkinsonism and Lewy body dementia, and E46K creates more pathogenic fibrils in vitro. Understanding the effect of these hereditary mutations on α-synuclein fibril structure is fundamental to α-synuclein biology. We therefore determined the cryo-electron microscopy (cryo-EM) structure of α-synuclein fibrils containing the hereditary E46K mutation. The 2.5-Å structure reveals a symmetric double protofilament in which the molecules adopt a vastly rearranged, lower energy fold compared to wild-type fibrils. We propose that the E46K misfolding pathway avoids electrostatic repulsion between K46 and K80, a residue pair which form the E46-K80 salt bridge in the wild-type fibril structure. We hypothesize that, under our conditions, the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge diverts α-synuclein into a kinetic trap-a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.
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