ArticleProceedings of the National Academy of Sciences of the United States of America2020
Unroofing site-specific α-synuclein-lipid interactions at the plasma membrane.
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 39 papers.
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Who cites it
39 citing papers in PubMed, 54 citations in OpenAlex.
- Proteoform-Resolved Cross-Linking Reveals Environment-Dependent Structural Effects of α-Synuclein S129 Phosphorylation.Journal of the American Chemical Society · 2026Article
- Membrane Phase, Charge, and Curvature Regulate α-Synuclein Binding Dynamics.bioRxiv : the preprint server for biology · 2026Article
- Cell-based regenerative interventions in Parkinson's disease: Overcoming pharmacological limitations.Acta pharmaceutica Sinica. B · 2026Review
- Syntaxin1A in synaptopathies: From molecular mechanisms to therapeutic implications in neurological disorders (Review).Biomedical reports · 2026Review
- Lipid membrane remodeling by myristic acid treatment reverses Parkinson's disease α-synuclein phenotypes in patient neurons.npj metabolic health and disease · 2026Article
- WDR44 drives de novo α-synuclein aggregation at the lysosomal membrane and promotes neuronal dysfunction in Parkinson's Disease.bioRxiv : the preprint server for biology · 2026Article
- The Progress of Active Immunotherapy for Parkinson's Disease.International journal of molecular sciences · 2026Review
- Plasma Membrane Lipid Composition and Turnover in Human Midbrain Neurons Investigated by Time-of-Flight Mass Spectrometry.Biomolecules · 2025Article
- Parkinson disease is a fatty acidopathy.Nature reviews. Neurology · 2025Review
- Alpha-synuclein modulates the positioning of endolysosomes in melanoma cells.Human molecular genetics · 2025Article
- Polymer sailing on rafts within lipid membranes.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Amyloid formation of alternatively spliced variants of α-synuclein.Protein science : a publication of the Protein Society · 2025Article
- Interplay between lipid droplets and alpha-synuclein: implication in Parkinson's disease pathogenesis.Frontiers in molecular neuroscience · 2025Review
- Alpha-synuclein aggregation induces prominent cellular lipid changes as revealed by Raman spectroscopy and machine learning analysis.Brain communications · 2025Article
- Interplay between Copper, Phosphatidylserine, and α-Synuclein Suggests a Link between Copper Homeostasis and Synaptic Vesicle Cycling.ACS chemical neuroscience · 2024Article
- Parkinson's disease-associated mutations in α-synuclein alters its lipid-bound state.Biophysical journal · 2024Article
- Lipid Metabolism Disorder in Cerebrospinal Fluid Related to Parkinson's Disease.Brain sciences · 2023Article
- Multiple tethers of organelle contact sites are involved in α-synuclein toxicity in yeast.Molecular biology of the cell · 2023Article
- The Parkinson-Associated Toxin Paraquat Shifts Physiological α-Synuclein Tetramers toward Monomers That Can Be Calpain-Truncated and Form Oligomers.The American journal of pathology · 2023Article
- AmyP53, a Therapeutic Peptide Candidate for the Treatment of Alzheimer's and Parkinson's Disease: Safety, Stability, Pharmacokinetics Parameters and Nose-to Brain Delivery.International journal of molecular sciences · 2022Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Parkinson's disease is associated with α-synuclein (α-syn), a cytosolic protein enriched in presynaptic terminals. The biological function of α-syn remains elusive; however, increasing evidence suggests that the protein is involved in the regulation of synaptic vesicle fusion, signifying the importance of α-syn-lipid interactions. We show that α-syn preferentially binds to GM1-rich, liquid-ordered lipid domains on cytoplasmic membranes by using unroofed cells, which encapsulates lipid complexity and cellular topology. Moreover, proteins (Rab3a, syntaxin-1A, and VAMP2) involved in exocytosis also localize with α-syn, supporting its proposed functional role in exocytosis. To investigate how these lipid/protein interactions influence α-syn at the residue level, α-syn was derivatized with an environmentally sensitive fluorophore (7-nitrobenz-2-oxa-1,3-diazol-4-yl [NBD]) at different N- and C-terminal sites. Measurements of NBD fluorescence lifetime distributions reveal that α-syn adopts a multitude of membrane-bound conformations, which were not recapitulated in simple micelle or vesicle models, indicating an exquisite sensitivity of the protein to the complex lipid environment. Interestingly, these data also suggest the participation of the C terminus in membrane localization, which is generally overlooked and thus emphasize the need to use cellularly derived and biologically relevant membranes for biophysical characterization. Collectively, our results demonstrate that α-syn is more conformationally dynamic at the membrane interface than previously appreciated, which may be important for both its physiological and pathological functions.
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