ArticleThe Journal of biological chemistry2023
Cryo-EM structure of amyloid fibril formed by α-synuclein hereditary A53E mutation reveals a distinct protofilament interface.
Article in The Journal of biological chemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 43 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
- In Vitro-Prepared A30P Alpha-Synuclein Fibrils Adopt the Conserved and Disease-Relevant Greek Key Fold.The journal of physical chemistry. B · 2026Article
- PET imaging of alpha-synuclein: from radiotracer design through in vitro and in vivo translation.European journal of nuclear medicine and molecular imaging · 2026Review
- Article
- When Proteins Go MAD-Misfolded, Amplified, Detected: Advances in α-Synuclein Pathophysiology and RT-QuIC Detection.Molecular neurobiology · 2026Review
- Thermodynamic stability modulates chaperone-mediated disaggregation of α-synuclein fibrils.Chemical science · 2026Article
- Hidden faces of alpha-synuclein: Cryo-EM revelation of fibril polymorphs driven by disease, mutations, and PTMs.BBA advances · 2026Review
- AI-Guided Dual Strategy for Peptide Inhibitor Design Targeting Structural Polymorphs of α-Synuclein Fibrils.Cells · 2025Article
- Pathological and Functional Brain Amyloids: A New Concept Explaining the Differences.International journal of molecular sciences · 2025Review
- Is synuclein aggregation a derived or ancestral trait? Ancestral sequence reconstruction uncovers stepwise evolution of synuclein aggregation.bioRxiv : the preprint server for biology · 2025Article
- Alpha-synuclein fibril structures cluster into distinct classes.Biophysical journal · 2025Review
- Ligands for Protein Fibrils of Amyloid-β, α-Synuclein, and Tau.Chemical reviews · 2025Review
- Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation.Nature communications · 2025Article
- Strategies of positron emission tomography (PET) tracer development for imaging of tau and α-synuclein in neurodegenerative disorders.RSC medicinal chemistry · 2025Review
- Solid-state NMR assignment of α-synuclein polymorph prepared from helical intermediate.Biomolecular NMR assignments · 2024Article
- Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases.Science advances · 2024Article
- Article
- Structure of Amyloid Peptide Ribbons Characterized by Electron Microscopy, Atomic Force Microscopy, and Solid-State Nuclear Magnetic Resonance.The journal of physical chemistry. B · 2024Article
- Ultrastructures of α-Synuclein Filaments in Synucleinopathy Brains and Experimental Models.Journal of movement disorders · 2024Article
- Elucidation of Secondary Structure and Toxicity of α-Synuclein Oligomers and Fibrils Grown in the Presence of Phosphatidylcholine and Phosphatidylserine.ACS chemical neuroscience · 2023Article
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10 authors at 4 institutions in 1 country.
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Abstract
Synucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA), have the same pathologic feature of misfolded α-synuclein protein (α-syn) accumulation in the brain. PD patients who carry α-syn hereditary mutations tend to have earlier onset and more severe clinical symptoms than sporadic PD patients. Therefore, revealing the effect of hereditary mutations to the α-syn fibril structure can help us understand these synucleinopathies' structural basis. Here, we present a 3.38 Å cryo-electron microscopy structure of α-synuclein fibrils containing the hereditary A53E mutation. The A53E fibril is symmetrically composed of two protofilaments, similar to other fibril structures of WT and mutant α-synuclein. The new structure is distinct from all other synuclein fibrils, not only at the interface between proto-filaments, but also between residues packed within the same proto-filament. A53E has the smallest interface with the least buried surface area among all α-syn fibrils, consisting of only two contacting residues. Within the same protofilament, A53E reveals distinct residue re-arrangement and structural variation at a cavity near its fibril core. Moreover, the A53E fibrils exhibit slower fibril formation and lower stability compared to WT and other mutants like A53T and H50Q, while also demonstrate strong cellular seeding in α-synuclein biosensor cells and primary neurons. In summary, our study aims to highlight structural differences - both within and between the protofilaments of A53E fibrils - and interpret fibril formation and cellular seeding of α-synuclein pathology in disease, which could further our understanding of the structure-activity relationship of α-synuclein mutants.
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