ArticleProceedings of the National Academy of Sciences of the United States of America2022
α-Synuclein phosphorylation at serine 129 occurs after initial protein deposition and inhibits seeded fibril formation and toxicity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers, 1 of them a synthesis that pooled it.
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Who cites it
111 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Are Therapies That Target α-Synuclein Effective at Halting Parkinson's Disease Progression? A Systematic Review.International journal of molecular sciences · 2023Pooled it
- 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
- TogoPhosTAC as a delivery-ready platform for targeted protein dephosphorylation.Nature communications · 2026Article
- Lipid droplets promote aberrant liquid-liquid phase separation of alpha-synuclein impairing energy homeostasis.EMBO reports · 2026Article
- Large-scale bidirectional arrayed genetic screens identify OXR1 and EMC4 as modifiers of αSynuclein aggregation.FEBS open bio · 2026Article
- From synaptic development to degeneration: a narrative review of small molecule strategies targeting alpha-synuclein in Parkinson's disease.Metabolic brain disease · 2026Review
- Development of an RNA aptamer as a therapeutic agent for synucleinopathies.Nature communications · 2026Article
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- Authentic Phosphorylation of α-Synuclein at Ser129 Reveals Functional Differences Not Captured by the S129D Phosphomimetic.ACS chemical biology · 2026Article
- Molecular profiling of alpha-synuclein pathology and seeding activity in Parkinson's disease.Acta neuropathologica · 2026Article
- A53T α-Synuclein Expression is Associated with Altered Dopaminergic-Like Differentiation and Reduced DNA Topoisomerase IIβ Levels in an In Vitro Model of Parkinson's Disease.Molecular neurobiology · 2026Article
- High molecular weight insoluble parkin in the substantia nigra of patients with idiopathic Parkinson's disease.NPJ Parkinson's disease · 2026Article
- Homocysteine increases phosphorylation and aggregation of α-synuclein.Journal of clinical biochemistry and nutrition · 2026Article
- Lipid Acyl Chain-Driven α-Synuclein Fibril Polymorphisms and Neuronal Pathologies.ACS chemical neuroscience · 2026Article
- 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
- A Degron Decoy System Co-opts Pathological Seeding to Enable Clearance of Multimeric α-Synuclein.bioRxiv : the preprint server for biology · 2026Article
- Alpha-synuclein overexpression triggers divergent cellular responses and post-translational modifications in SH-SY5Y and ReNcell VM models.Cellular and molecular life sciences : CMLS · 2026Article
- Cross-Linking and Covalent Labeling Mass Spectrometry Reveal Proteoform-Driven Conformational Changes in Alpha Synuclein.Analytical chemistry · 2026Article
- Phosphorylation of α‑Synuclein Fibrils at S129 Changes DNAJB1 Binding as Probed by Solid-State NMR.JACS Au · 2026Article
- When Proteins Go MAD-Misfolded, Amplified, Detected: Advances in α-Synuclein Pathophysiology and RT-QuIC Detection.Molecular neurobiology · 2026Review
51 more citing papers are in PubMed but not listed here.
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Authors and funding
21 authors.
Funding
Abstract
α-Synuclein (α-syn) phosphorylation at serine 129 (pS129–α-syn) is substantially increased in Lewy body disease, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, the pathogenic relevance of pS129–α-syn remains controversial, so we sought to identify when pS129 modification occurs during α-syn aggregation and its role in initiation, progression and cellular toxicity of disease. Using diverse aggregation assays, including real-time quaking-induced conversion (RT-QuIC) on brain homogenates from PD and DLB cases, we demonstrated that pS129–α-syn inhibits α-syn fibril formation and seeded aggregation. We also identified lower seeding propensity of pS129–α-syn in cultured cells and correspondingly attenuated cellular toxicity. To build upon these findings, we developed a monoclonal antibody (4B1) specifically recognizing nonphosphorylated S129–α-syn (WT–α-syn) and noted that S129 residue is more efficiently phosphorylated when the protein is aggregated. Using this antibody, we characterized the time-course of α-syn phosphorylation in organotypic mouse hippocampal cultures and mice injected with α-syn preformed fibrils, and we observed aggregation of nonphosphorylated α-syn followed by later pS129–α-syn. Furthermore, in postmortem brain tissue from PD and DLB patients, we observed an inverse relationship between relative abundance of nonphosphorylated α-syn and disease duration. These findings suggest that pS129–α-syn occurs subsequent to initial protein aggregation and apparently inhibits further aggregation. This could possibly imply a potential protective role for pS129–α-syn, which has major implications for understanding the pathobiology of Lewy body disease and the continued use of reduced pS129–α-syn as a measure of efficacy in clinical trials.
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