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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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“Although αsynuclein has been classically described to have an unfolded tertiary structure and to be present as monomers that acquire an α-helical secondary structure upon binding to lipid membranes [26,27], recent reports suggest that α-synuclein natively forms α-helically folded tetramers when isolated under non-dena…”
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“Moreover, increased GluCer was also shown to de-stabilize aSyn tetramers (Kim et al., 2018), which in contrast to oligomers are proposed to represent physiological multimeric forms less prone to aggregate (Bartels et al., 2011; Dettmer et al., 2015), although this is still controversial.”
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“By contrast, a recent study demonstrated that -syn can exist as a tetramer in vivo that does not form fibrils [52], suggesting that not all types of oligomers can seed formation of fibrillar -syn.”
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“Finally, the highest affinity site for Cu(II) is located at the N-terminus of AS, where the metal ion is anchored by the NH2 group, a deprotonated backbone amide, the carboxylate group belonging to Asp2 and a water molecule, yielding a 2N2O equatorial coordination mode (Fig.”
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Sahoo, S., Padhy, A. A., Kumari, V., & Mishra, P. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02897-1 · Cited by 82
“Tetrameric forms of α-synuclein are resistant to aggregation, but genetic and/ or environmental factors are known to trigger its disassembly and initiate misfolding rendering it prone to form higher order oligomers [40].”
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“However, a recent report now hints at a more complex picture as the predominant physiological species of α-syn is a helically folded tetramer (Bartels et al., 2011). α-Syn is, however, intrinsically defined as an aggregationprone protein.”
BackgroundInteractions between Calcium and Alpha-Synuclein in Neurodegeneration
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“Recently, using both non-denaturing gel electrophoresis and MALDI-TOF mass spectroscopy, α-syn has been shown to exist as α-syn tetramers in M17D, HEK293, HeLa and COS-7 cells [44,45], with predominantly helical structure.”
MethodFinkelstein, D. I., Hare, D. J., Billings, J. L., Sedjahtera, A., Nurjono, M., Arthofer, E., George, S., Culvenor, J. G., Bush, A. I., & Adlard, P. A. (2015) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5b00253 · Cited by 79
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“While α-Syn monomer is unstructured and has the potential to form amyloid aggregates (4–6), multiple studies suggested that it forms α-helical tetramers physiologically that resist aggregation (7, 8).”
Backgroundγ-Synuclein: Seeding of α-Synuclein Aggregation and Transmission between Cells
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“Nevertheless, αSyn has been isolated in several conformational states, mainly as a tetramer, from various cell types [34,35].”
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Synucleins: New Data on Misfolding, Aggregation and Role in Diseases
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“α-Synuclein-containing protein inclusions, aggregates, and fibrils are found in neuropathological inclusions in neurons and glia of patients with synucleinopathies [28].”
BackgroundIncreased α-synuclein phosphorylation and nitration in the aging primate substantia nigra
McCormack, A. L., Mak, S. K., & Monte, D. A. D. (2012) · Cell Death and Disease · doi:10.1038/cddis.2012.50 · Cited by 80
Conformational Propensities of Intrinsically Disordered Proteins from NMR Chemical Shifts
Kragelj, J., Ozenne, V., Blackledge, M. J., & Jensen, M. R. (2013) · ChemPhysChem · doi:10.1002/cphc.201300387 · Cited by 79
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“The protein is 140 amino acids in length (Figure 1), occurs as a helically folded tetramer under physiological conditions (Bartels et al., 2011) and is able to form oligomers, fibrils and more complex aggregates, eventually leading to Lewy bodies.”
BackgroundA Revised Picture of the Cu(II)−α-Synuclein Complex: The Role of N-Terminal Acetylation
Moriarty, G. M., Minetti, C. A. S. A., Remeta, D. P., & Baum, J. (2014) · Biochemistry · doi:10.1021/bi5003025 · Cited by 79
Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts
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α‐Synuclein as an intrinsically disordered monomer – fact or artefact?
Cerqueira, E. C., Gonçalves, P. D. C., Pinheiro, A. S., Cortines, J. R., & Follmer, C. (2013) · FEBS Journal · doi:10.1111/febs.12471 · Cited by 80
“To determine whether α-syn dimers are irreversibly dissociated by heating as found for the helicoidal tetramer [9], α-syn samples were boiled for 5 min, cooled in an ice bath and then cross-linked immediately (labeled as 1 min) or 10 or 30 min after the boiling procedure (Figure 3G).”
InfluentialRelease and uptake of pathologic alpha-synuclein
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Steele, J., Ju, S., Lachenmayer, M. L., Liken, J., Stock, A., Kim, S. Y., Delgado, L. M., Alfaro, I. E., Bernales, S., Verdile, G., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.115 · Cited by 82
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α-Synuclein fibril-specific nanobody reduces prion-like α-synuclein spreading in mice
Butler, Y. R., Liu, Y., Kumbhar, R., Zhao, P., Gadhave, K., Wang, N., Li, Y., Mao, X., & Wang, W. (2022) · Nature Communications · doi:10.1038/s41467-022-31787-2 · Cited by 80
Evidence of Native α-Synuclein Conformers in the Human Brain
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The link between the SNCA gene and parkinsonism
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The Promise and Challenges of Developing miRNA-Based Therapeutics for Parkinson’s Disease
Titze-de-Almeida, S. S., Soto‐Sánchez, C., Fernández, E., Koprich, J. B., Brotchie, J. M., & Titze‐de‐Almeida, R. (2020) · Cells · doi:10.3390/cells9040841 · Cited by 81
Golgi fragmentation is Rab and SNARE dependent in cellular models of Parkinson’s disease
Rendón, W. O., Martínez‐Alonso, E., Tomás, M., Martínez-Martínez, N., & Martínez‐Menárguez, J. A. (2012) · Histochemistry and Cell Biology · doi:10.1007/s00418-012-1059-4 · Cited by 79
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Αlpha-Synuclein as a Mediator in the Interplay between Aging and Parkinson’s Disease
Bobela, W., Aebischer, P., & Schneider, B. L. (2015) · Biomolecules · doi:10.3390/biom5042675 · Cited by 75
Serebryany, E., Woodard, J. C., Adkar, B. V., Shabab, M., King, J. W., & Shakhnovich, E. I. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.735977 · Cited by 75
Mechanisms of alpha-synuclein toxicity: An update and outlook
Brás, I. C., Xylaki, M., & Outeiro, T. F. (2019) · Progress in brain research · doi:10.1016/bs.pbr.2019.10.005 · Cited by 78
Oiwa, K., Watanabe, S., Onodera, K., Iguchi, Y., Kinoshita, Y., Komine, O., Sobue, A., Okada, Y., Katsuno, M., & Yamanaka, K. (2023) · Science Advances · doi:10.1126/sciadv.adf6895 · Cited by 75
Intracellular Dynamics of Synucleins
Surguchov, A. P. (2015) · International review of cytology · doi:10.1016/bs.ircmb.2015.07.007 · Cited by 77
ELISA method to detect α-synuclein oligomers in cell and animal models
Lassen, L. B., Gregersen, E., Isager, A. K., Betzer, C., Kofoed, R. H., & Jensen, P. H. (2018) · PLoS ONE · doi:10.1371/journal.pone.0196056 · Cited by 75
Modeling Parkinson’s Disease Using Induced Pluripotent Stem Cells
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Sardi, S. P., Cheng, S. H., & Shihabuddin, L. S. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2014.12.001 · Cited by 75
Gangliosides, α-Synuclein, and Parkinson's Disease
Ledeen, R. W., & Wu, G. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2017.12.009 · Cited by 73
Subcellular localization of alpha-synuclein aggregates and their interaction with membranes
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“This αS tetramer is in a dynamic equilibrium with the unfolded monomer, which on the contrary is more susceptible to aggregation (Bartels et al., 2011).”
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Mollenhauer, B., Parnetti, L., Rektorová, I., Kramberger, M. G., Pikkarainen, M., Schulz‐Schaeffer, W., Aarsland, D., Svenningsson, P., Farotti, L., Verbeek, M. M., et al. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13390 · Cited by 73
“With the recent rise in research interest in the physiological conformation of a-syn in biological systems (Bartels et al. 2011) and a prion-like propagation of a-syn aggregates from affected neurons to healthy ones in multiple disease paradigms (including to cells that are present since birth as well as those grafted…”
BackgroundKuwahara, T., Tonegawa‐Kuji, R., Ito, G., Mitani, S., & Iwatsubo, T. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.237131 · Cited by 74
Luth, E. S., Bartels, T., Dettmer, U., Kim, N. C., & Selkoe, D. J. (2014) · Biochemistry · doi:10.1021/bi501188a · Cited by 77
Self-citationHigh Stability and Cooperative Unfolding of α-Synuclein Oligomers
Pasławski, W., Andreasen, M., Nielsen, S. B., Lorenzen, N., Thomsen, K., Kaspersen, J. D., Pedersen, J. S., & Otzen, D. E. (2014) · Biochemistry · doi:10.1021/bi5007833 · Cited by 73
Angarica, V. E., Ventura, S., & Sancho, J. (2013) · BMC Genomics · doi:10.1186/1471-2164-14-316 · Cited by 74
“However, it is still a matter of debate whether these two proteins are disordered or contain a significant α-helical content [71,72].”
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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