ArticleNature communications2024
Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 55 citations in OpenAlex.
- Neurotoxicity, α-synuclein pathology, and mitochondrial dysfunction: A comparative study of different mouse models of Parkinson's disease.Neural regeneration research · 2026Article
- 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
- Structural Hierarchy and Maturation of Amyloid Fibrils Revealed by Interface Descriptor Analysis.Journal of chemical information and modeling · 2026Article
- No Significant Secondary Structural Change of α-Synuclein Monomer by Site-Specific DOPA or Phosphorylation Introduction in Its C-Terminal Region.Journal of peptide science : an official publication of the European Peptide Society · 2026Article
- Recent advancements in sample pretreatment methods for glycoproteomics.Biophysics reports · 2026Article
- Amyloid fibril polymorphism: Structural mechanisms of assembly and the links to disease.Current opinion in structural biology · 2026Review
- PET imaging of alpha-synuclein: from radiotracer design through in vitro and in vivo translation.European journal of nuclear medicine and molecular imaging · 2026Review
- A versatile platform for sequential glyco-, phospho-, and proteomics with multi-PTMs integration.Nature communications · 2026Article
- When Proteins Go MAD-Misfolded, Amplified, Detected: Advances in α-Synuclein Pathophysiology and RT-QuIC Detection.Molecular neurobiology · 2026Review
- Regulatory mechanism of O-linked N-acetylglucosamine protein modification on autophagy in cancer.Clinical and translational medicine · 2026Review
- Hidden faces of alpha-synuclein: Cryo-EM revelation of fibril polymorphs driven by disease, mutations, and PTMs.BBA advances · 2026Review
- Synaptic Vesicle Disruption in Parkinson's Disease: Dual Roles of α-Synuclein and Emerging Therapeutic Targets.Brain sciences · 2025Review
- Genetic code expansion and enzymatic modifications as accessible methods for studying site-specific post-translational modifications of alpha-synuclein and tau.Protein science : a publication of the Protein Society · 2025Article
- Investigation of All Disease-Relevant Lysine Acetylation Sites in α-Synuclein Enabled by Non-canonical Amino Acid Mutagenesis.bioRxiv : the preprint server for biology · 2025Article
- Alpha-synuclein fibril structures cluster into distinct classes.Biophysical journal · 2025Review
- Design of Ig-like binders targeting α-synuclein fibril for mitigating its pathological activities.Nature communications · 2025Article
- Synaptic vesicle-omics in mice captures signatures of aging and synucleinopathy.Nature communications · 2025Article
- Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation.Nature communications · 2025Article
- Kinetic Steering of Amyloid Formation and Polymorphism by Canagliflozin, a Type-2 Diabetes Drug.Journal of the American Chemical Society · 2025Article
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
α-Synuclein forms amyloid fibrils that are critical in the progression of Parkinson's disease and serves as the pathological hallmark of this condition. Different posttranslational modifications have been identified at multiple sites of α-synuclein, influencing its conformation, aggregation and function. Here, we investigate how disease-related phosphorylation and O-GlcNAcylation at the same α-synuclein site (S87) affect fibril structure and neuropathology. Using semi-synthesis, we obtained homogenous α-synuclein monomer with site-specific phosphorylation (pS87) and O-GlcNAcylation (gS87) at S87, respectively. Cryo-EM revealed that pS87 and gS87 α-synuclein form two distinct fibril structures. The GlcNAc situated at S87 establishes interactions with K80 and E61, inducing a unique iron-like fold with the GlcNAc molecule on the iron handle. Phosphorylation at the same site prevents a lengthy C-terminal region including residues 73 to 140 from incorporating into the fibril core due to electrostatic repulsion. Instead, the N-terminal half of the fibril (1-72) takes on an arch-like fibril structure. We further show that both pS87 and gS87 α-synuclein fibrils display reduced neurotoxicity and propagation activity compared with unmodified α-synuclein fibrils. Our findings demonstrate that different posttranslational modifications at the same site can produce distinct fibril structures, which emphasizes link between posttranslational modifications and amyloid fibril formation and pathology.
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