ArticleNature chemical biology2024
O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology.
Article in Nature chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 47 papers.
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47 citing papers in PubMed, 75 citations in OpenAlex.
- Apoptin-Derived Peptide Alleviates Temporal Lobe Epilepsy (TLE) by Limiting Neuronal CaCNS neuroscience & therapeutics · 2026Article
- O-GlcNAcylation: A molecular switch linking brain health to neurodegeneration.Neural regeneration research · 2026Article
- Structural Hierarchy and Maturation of Amyloid Fibrils Revealed by Interface Descriptor Analysis.Journal of chemical information and modeling · 2026Article
- Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation.Brain sciences · 2026Review
- Effects of Site-Specific Glycation on α-Synuclein.ACS chemical biology · 2026Article
- Modeling Parkinson's pathology in human iPSC dopaminergic neurons uncovers key mechanisms of Lewy body formation and heterogeneity.Science advances · 2026Article
- Functional Engineering of Bioactive Peptides: Chemical Modifications and Synthetic Biology Approaches.International journal of molecular sciences · 2026Review
- Chemoenzymatic Labeling Method for Detection of O-GlcNAcylated α-Synuclein Proteins by Western Blot.Bio-protocol · 2026Article
- Reverse-engineering amyloid strains with generative protein design.bioRxiv : the preprint server for biology · 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
- Protein-encapsulated fluorogenic probes for the selective detection of endogenous O-GlcNAcase (OGA).Chemical science · 2026Article
- Revealing and Exploiting the Biochemistry ofBiochemistry · 2026Review
- Pharmacological inhibition of O-GlcNAcase reduces pS129-α-synuclein positive aggregates in the substantia nigra of mThy1-hSNCA mice.Journal of Parkinson's disease · 2026Article
- Seeing the Unseen: Super-Resolution Microscopy in Protein Aggregation Research.Chemical & biomedical imaging · 2026Review
- Cross-Linking and Covalent Labeling Mass Spectrometry Reveal Proteoform-Driven Conformational Changes in Alpha Synuclein.Analytical chemistry · 2026Article
- Highly sensitive chemiluminescence imaging of misfolded proteins in neurodegenerative models.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- 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
- Discovery of Sennoside A as a NaturalResearch (Washington, D.C.) · 2026Article
Corrections and comments
- Erratum issued
- Update of
Authors and funding
16 authors at 4 institutions in 2 countries.
Funding
Abstract
Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with distinct toxic properties, seeding activities and pathology. Understanding the determinants contributing to the formation of different amyloid features could open new avenues for developing disease-specific diagnostics and therapies. Here we report that O-GlcNAc modification of α-synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by cryogenic electron microscopy, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson's disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc-modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that posttranslational modifications, such as O-GlcNAc modification, of α-synuclein are key determinants of α-synuclein amyloid strains and pathogenicity.
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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.