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α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation
Open accessAbstract
Parkinson's disease is the second most common neurodegenerative disorder. Growing evidence indicates a causative role of misfolded forms of the protein α-synuclein in the pathogenesis of Parkinson's disease. Intraneuronal aggregates of α-synuclein occur in Lewy bodies and Lewy neurites, the cytopathological hallmarks of Parkinson's disease and related disorders called synucleinopathies. α-Synuclein has long been defined as a 'natively unfolded' monomer of about 14 kDa (ref. 6) that is believed to acquire α-helical secondary structure only upon binding to lipid vesicles. This concept derives from the widespread use of recombinant bacterial expression protocols for in vitro studies, and of overexpression, sample heating and/or denaturing gels for cell culture and tissue studies. In contrast, we report that endogenous α-synuclein isolated and analysed under non-denaturing conditions from neuronal and non-neuronal cell lines, brain tissue and living human cells occurs in large part as a folded tetramer of about 58 kDa. Several methods, including analytical ultracentrifugation, scanning transmission electron microscopy and in vitro cell crosslinking confirmed the occurrence of the tetramer. Native, cell-derived α-synuclein showed α-helical structure without lipid addition and had much greater lipid-binding capacity than the recombinant α-synuclein studied heretofore. Whereas recombinantly expressed monomers readily aggregated into amyloid-like fibrils in vitro, native human tetramers underwent little or no amyloid-like aggregation. On the basis of these findings, we propose that destabilization of the helically folded tetramer precedes α-synuclein misfolding and aggregation in Parkinson's disease and other human synucleinopathies, and that small molecules that stabilize the physiological tetramer could reduce α-synuclein pathogenicity.
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“in human brain lysates, human neuronal cultures, mouse models, and in mouse/human/goat cell lines expressing familial PD αSyn mutations (A53T or E46K), a decrease in the tetramer:monomer ratio correlated to increased neurotoxicity”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [136]
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“Under normal physiological conditions, aSyn occurs as a a-helix rich tetramer that is not prone to aggregation (Bartels et al. 2011).”
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“Upon destabilization, this leads to the misfolding and aggregation of α-syn in neurons (Ruipérez et al., 2010; Bartels et al., 2011; Broersen et al., 2018).”
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“Very recently, a helically folded tetramer of the soluble protein has been described in equilibrium with the monomer (Bartels et al., 2011; Wang et al., 2011; Fanning et al., 2018).”
BackgroundThe Interplay between Alpha-Synuclein Clearance and Spreading
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“cell lines and mouse brain tissue revealed that a-syn might exist as a folded, stable tetramer with a molecular weight of about 58 kDa (5, 76).”
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“a natively folded tetramer (30, 31), but further experimentation, including in-cell NMR (29, 72), indicate that S is an unfolded monomer in vivo.”
BackgroundVersatile Structures of α-Synuclein
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“…bundle structure that were evidenced by multiple approaches including native PAGE, cross linking, transmission electron microscopy (TEM), scanning transmission electron microscopy (STEM) and sedimentation equilibrium analytical ultracentrifugation (SE-AUC; Chen et al., 2007; Bartels et al., 2011).”
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The Dynamic Structure of α-Synuclein Multimers
Gurry, T., Ullman, O., Fisher, C. K., Perovic, I., Pochapsky, T. C., & Stultz, C. M. (2013) · Journal of the American Chemical Society · doi:10.1021/ja310518p · Cited by 110
Analysis of Protein Aggregation in Neurodegenerative Disease
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New insights on the structure of alpha-synuclein fibrils using cryo-electron microscopy
Guerrero-Ferreira, R., Kováčik, Ľ., Ni, D., & Stahlberg, H. (2020) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2020.01.014 · Cited by 109
Poststroke Induction of -Synuclein Mediates Ischemic Brain Damage
Kim, T., Mehta, S. L., Kaimal, B., Lyons, K. E., Dempsey, R. J., & Vemuganti, R. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1241-16.2016 · Cited by 104
“Under native conditions, -Syn is known to exist as a helically folded tetramer that resists aggregation (Bartels et al., 2011).”
BackgroundLoss of amino-terminal acetylation suppresses a prion phenotype by modulating global protein folding
Holmes, W. M., Mannakee, B. K., Gutenkunst, R. N., & Serio, T. R. (2014) · Nature Communications · doi:10.1038/ncomms5383 · Cited by 106
Can Parkinson's disease pathology be propagated from one neuron to another?
Dunning, C. J. R., Reyes, J. F., Steiner, J. A., & Brundin, P. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.11.003 · Cited by 111
“neuronal and non-neuronal sources under non-denaturing conditions, it is a folded tetramer (Bartels et al., 2011).”
InfluentialLipid and immune abnormalities causing age-dependent neurodegeneration and Parkinson’s disease
Hallett, P. J., Engelender, S., & Ole Isacson, A. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1532-2 · Cited by 105
“Cross-linking studies have identified a physiological conformation of α-synuclein in α-helically folded tetramers [54], which are hypothesized to be in equilibrium with unfolded α-synuclein monomers [55].”
BackgroundImberdis, T., Negri, J. M., Ramalingam, N., Terry-Kantor, E., Ho, G. P. H., Fanning, S., Stirtz, G. L., Kim, T., Levy, O. A., Young‐Pearse, T. L., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1903216116 · Cited by 102
“The increase in physiologically soluble αS upon SCD inhibition is associated with increased tetramer/multimer formation, an event known to prevent αS aggregation/toxicity (8, 51).”
Self-citationAdsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics
Hellstrand, E., Grey, M., Ainalem, M.-L., Ankner, J. F., Forsyth, V. T., Fragneto, G., Haertlein, M., Dauvergne, M.-T., Nilsson, H., Brundin, P., et al. (2013) · ACS Chemical Neuroscience · doi:10.1021/cn400066t · Cited by 102
α-Synuclein pathology as a target in neurodegenerative diseases
Park, H.-J., Kam, T., Dawson, V. L., & Dawson, T. M. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-01043-w · Cited by 121
“Nitration . α-Synuclein can be nitrated at tyrosine residues 125, 133 and 136 in the C terminus and at tyrosine residue 39 in the N terminus 94 .”
The usual suspects, dopamine and alpha‐synuclein, conspire to cause neurodegeneration
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“In 2011, two groups published results indicating that α-synuclein exists natively as multimers with tetramers as the most abundant conformation.(75,76) However, subsequent in-cell NMR analysis of α-synuclein in E.”
BackgroundThe Contribution of Iron to Protein Aggregation Disorders in the Central Nervous System
Joppe, K., Roser, A., Maass, F., & Lingor, P. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00015 · Cited by 103
Transmission of α-synuclein seeds in neurodegenerative disease: recent developments
Karpowicz, R. J., Trojanowski, J. Q., & Lee, V. M. ‐. (2019) · Laboratory Investigation · doi:10.1038/s41374-019-0195-z · Cited by 105
“Although controversial, it has been demonstrated that α-syn can exist in solution as a stable tetrameric unit and that this association could protect cells from aggregation of α-syn into pathological species via sequestration of monomer [69].”
BackgroundSynucleinopathies: Where we are and where we need to go
Brás, I. C., Dominguez‐Meijide, A., Gerhardt, E., Koss, D. J., Lázaro, D. F., Santos, P. I., Vasili, E., Xylaki, M., & Outeiro, T. F. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.14965 · Cited by 106
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In‐Cell NMR and EPR Spectroscopy of Biomacromolecules
Hänsel, R., Luh, L. M., Corbeski, I., Trantı́rek, L., & Dötsch, V. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201311320 · Cited by 102
Sorting out release, uptake and processing of alpha‐synuclein during prion‐like spread of pathology
Tyson, T., Steiner, J. A., & Brundin, P. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13449 · Cited by 110
“Multimeric forms of a-syn, principally tetrameric, have been isolated from neuronal and non-neuronal cell lines, brain tissue, and living human cells (Bartels et al. 2011; Wang et al. 2011; Burr e et al. 2014).”
BackgroundDettmer, U., Ramalingam, N., von Saucken, V. E., Kim, T., Newman, A. J., Terry-Kantor, E., Nuber, S., Ericsson, M., Fanning, S., Bartels, T., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx227 · Cited by 102
Self-citationFonseca‐Ornelas, L., Eisbach, S. E., Paulat, M., Giller, K., Fernández, C. O., Outeiro, T. F., Becker, S., & Zweckstetter, M. (2014) · Nature Communications · doi:10.1038/ncomms6857 · Cited by 99
The crowd you're in with: Effects of different types of crowding agents on protein aggregation
Breydo, L., Reddy, K. D., Piai, A., Felli, I. C., Pierattelli, R., & Uversky, V. N. (2013) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2013.11.004 · Cited by 102
Waudby, C. A., Camilloni, C., Fitzpatrick, A. W. P., Cabrita, L. D., Dobson, C. M., Vendruscolo, M., & Christodoulou, J. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072286 · Cited by 101
α-Synuclein: A Multifunctional Player in Exocytosis, Endocytosis, and Vesicle Recycling
Huang, M., Wang, B., Li, X., Fu, C., Wang, C., & Kang, X. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00028 · Cited by 106
“Whereas, recent evidence shows that mature fibrils are non-toxic, and even the toxicity of the oligomers depends on the amount of β-sheet content in the rigid regions of them (Bartels et al., 2011; Cremades et al., 2012; Fusco et al., 2017).”
BackgroundThe remarkable conformational plasticity of alpha-synuclein: blessing or curse?
Deleersnijder, A., Gérard, M., Debyser, Z., & Baekelandt, V. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.04.002 · Cited by 104
Yu, H., Han, W., Ma, W., & Schulten, K. J. (2015) · The Journal of Chemical Physics · doi:10.1063/1.4936910 · Cited by 99
α-Synuclein is a Novel Microtubule Dynamase
Cartelli, D., Aliverti, A., Barbiroli, A. G., Santambrogio, C., Ragg, E. M., Casagrande, F., Cantele, F., Beltramone, S., Marangon, J., Gregorio, C. D., et al. (2016) · Scientific Reports · doi:10.1038/srep33289 · Cited by 104
Loss of Functional Alpha-Synuclein: A Toxic Event in Parkinson's Disease?
Kanaan, N. M., & Manfredsson, F. P. (2012) · Journal of Parkinson s Disease · doi:10.3233/jpd-012138 · Cited by 104
“are generated through different pathways [20, 21].”
BackgroundAlpha-synuclein: a pathological factor with Aβ and tau and biomarker in Alzheimer’s disease
Shim, K. H., Kang, M. J., Youn, Y. C., An, S. S. A., & Kim, S. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01150-0 · Cited by 106
“However, purified native α-syn from human erythrocytes exists in the form of a tetramer with an α-helical structure, which could resist self-aggregation into protofibril/ fibril conformations [28].”
Background
Metadata
- Authors
- Bartels, T., Choi, J. G., & Selkoe, D. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Selkoe, Dennis J.
- Venue
- Nature
- Published
- 2011-08-14
- Volume
- 477
- Issue
- 7362
- Pages
- 107-110
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3166366
- OpenAlex
- W2026717532
- Cited by
- 1,263
- References
- 24
- Citations by year
- 2026: 48 · 2025: 71 · 2024: 81 · 2023: 65 · 2022: 93 · 2021: 81 · 2020: 89 · 2019: 96 · 2018: 83 · 2017: 98 · 2016: 79 · 2015: 83 · 2014: 86 · 2013: 95 · 2012: 99
- FWCI
- 59.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS051318, P50NS038375, NS051318, NS038375)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein, protein aggregation, Parkinson's disease, synucleinopathies, intrinsically disordered proteins, lipid binding, amyloid-like fibrils, tetramer stabilization, Lewy bodies, protein misfolding, neurodegeneration, brain tissue, neuronal cell lines
- MeSH terms
- Animals, Chlorocebus aethiops, Erythrocytes, Escherichia coli, HeLa Cells, Humans, Recombinant Proteins, Time Factors, Blotting, Western, Protein Folding, COS Cells, Cell Line, Tumor, Lipid Metabolism, Mice, alpha-Synuclein, HEK293 Cells
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