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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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“In this vein, the notion of a physiological tetramer that is resistant to aggregation [28,29] may provide novel opportunities, as it may lead to the development of tetramer stabilizing drugs to prevent a-Synuclein aggregation.”
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“This is an ideal test case for our chemical library because α-synuclein consists mostly of α-helices (∼65%), and its aggregation could be monitored in real-time (63, 64).”
BackgroundMolecular mechanisms of amyloid formation in living systems
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Hypothesis: A role for EBV-induced molecular mimicry in Parkinson's disease
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“Another possibility is disruption of the native tetrameric state of a-syn: Recent studies have challenged the widely-held notion that a-syn exists predominantly or exclusively as an unstructuredmonomer in its native state and have provided evidence that it may exist instead in a helically-folded tetrameric form [97,98…”
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BackgroundCanerina‐Amaro, A., Pereda, D., Díaz, M. L., Rodríguez‐Barreto, D., Casañas‐Sánchez, V., Heffer, M., Garcia‐Esparcia, P., Ferrer, I., Puertas‐Avendaño, R., & Marín, R. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00382 · Cited by 62
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“4A), suggesting that -syn (monomer, 14 kDa) proteins are most likely tetramers and octamers, consistent with -syn tetramers found in physiological conditions (Bartels et al., 2011).”
BackgroundArachidonic acid mediates the formation of abundant alpha-helical multimers of alpha-synuclein
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“S3A), in line with earlier observations (12, 14, 15).”
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“to be helical [63, 68, 69] and aggregation-resistant”
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“While the predominant view is that a-Syn exists as an unfolded monomer under native conditions, recent studies showed that a-Syn may exist as a helically folded tetramer that resists aggregation and fibrillation in the normal brain.(74,75) Neurons derived from PD patients expressing A53T mutant a-Syn contained decreas…”
BackgroundThe interaction of α-synuclein and Tau: A molecular conspiracy in neurodegeneration?
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Alpha synuclein in hematopoiesis and immunity
Pei, Y., & Maitta, R. W. (2019) · Heliyon · doi:10.1016/j.heliyon.2019.e02590 · Cited by 62
Small molecules interacting with α-synuclein: antiaggregating and cytoprotective properties
Marchiani, A., Mammi, S., Siligardi, G., Hussain, R., Tessari, I., Bubacco, L., Delogu, G., Fabbri, D., Dettori, M. A., Sanna, D., et al. (2013) · Amino Acids · doi:10.1007/s00726-013-1503-3 · Cited by 59
“This assumption is highly relevant in light of the recent results of Bartels et al. (2011) demonstrating that monomeric AS represents the least abundant species in normal cells, and that the predominant physiological species of AS in cells and brain is a helical folded tetramer, like transthyretin.”
BackgroundStructural Insights into Amyloid Oligomers of the Parkinson Disease-related Protein α-Synuclein
Gallea, J. I., & Celej, M. S. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.566695 · Cited by 61
Pirc, K., & Ulrih, N. P. (2015) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2015.06.021 · Cited by 64
Tauroursodeoxycholic acid (TUDCA) is neuroprotective in a chronic mouse model of Parkinson’s disease
Cuevas, E., Burks, S., Raymick, J., Robinson, B., Gómez-Crisóstomo, N. P., Escudero-Lourdes, C., Lopez, A. G. G., Chigurupati, S., Hanig, J., Ferguson, S. A., et al. (2022) · Nutritional Neuroscience · doi:10.1080/1028415x.2020.1859729 · Cited by 57
“without denaturization and not run in reduced conditions in order to determine protein expression of its aggregated form(s) [34].”
BackgroundLipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders
Erskine, D., Koss, D. J., Korolchuk, V. I., Outeiro, T. F., Attems, J., & McKeith, I. G. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02266-7 · Cited by 58
A Randomized First‐in‐Human Study With UB‐312, a UBITh® α‐Synuclein Peptide Vaccine
Yu, H. J., Thijssen, E., van Brummelen, E. M. J., van der Plas, J. L., Radanović, I., Moerland, M., Hsieh, E., Groeneveld, G. J., & Dodart, J. (2022) · Movement Disorders · doi:10.1002/mds.29016 · Cited by 66
“functions, and regulation of neurotransmitter release at the synapse.(3,4) Duplications, point mutations, or”
BackgroundEijsvogel, P. P. N. M., Misra, P., Concha‐Marambio, L., Boyd, J. D., Ding, S., Fedor, L., Hsieh, Y.-T., Sun, Y. S., Vroom, M. M., Farris, C. M., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-03101-8 · Cited by 58
“Expressed primarily in presynaptic terminals, αSyn is involved in synaptic vesicle trafficking and modulation and neurotransmitter regulation 2,3 .”
Kang, L., Janowska, M. K., Moriarty, G. M., & Baum, J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0075018 · Cited by 57
The Oligomer Hypothesis in α-Synucleinopathy
Ono, K. (2017) · Neurochemical Research · doi:10.1007/s11064-017-2382-x · Cited by 58
Iron Redox Chemistry Promotes Antiparallel Oligomerization of α-Synuclein
Abeyawardhane, D. L., Fernández, R. D., Murgas, C. J., Heitger, D. R., Forney, A. K., Crozier, M. K., & Lucas, H. R. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b02013 · Cited by 58
Birol, M., Wojcik, S. P., Miranker, A. D., & Rhoades, E. R. (2019) · PLoS Biology · doi:10.1371/journal.pbio.3000318 · Cited by 54
Baets, G. D., Doorn, L. V., Rousseau, F., & Schymkowitz, J. W. H. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004374 · Cited by 59
Mutations in LRRK2 impair NF-κB pathway in iPSC-derived neurons
de Maturana, R. L., Lang, V., Zubiarrain, A., Sousa, A., Vázquez, N., Gorostidi, A., Benitez, J. A., de Munaín, A. L., Rodríguez, M. S., & Sánchez‐Pernaute, R. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0761-x · Cited by 56
“In this study, TNFα transiently increased α-synuclein levels, which could eventually favor protein aggregation and pathogenicity [41, 42].”
BackgroundLi, D., Mastaglia, F. L., Fletcher, S., & Wilton, S. D. (2020) · Medicinal Research Reviews · doi:10.1002/med.21718 · Cited by 59
“As the main component of Lewy bodies, monomeric or α‐helically folded tetrameric α‐synuclein is actively degraded by the UPS under physiological conditions.(35,36) SNCA mutations, including duplication or triplication of the whole gene, or disease‐associated missense mutations, render α‐synuclein prone to misfolding a…”
BackgroundIntermediates of α-synuclein aggregation: Implications in Parkinson's disease pathogenesis
Gadhe, L. G., Sakunthala, A., Mukherjee, S., Gahlot, N., Bera, R., Sawner, A. S., Kadu, P., & Maji, S. K. (2021) · Biophysical Chemistry · doi:10.1016/j.bpc.2021.106736 · Cited by 56
α-Synuclein as a ferrireductase
Brown, D. R. (2013) · Biochemical Society Transactions · doi:10.1042/bst20130130 · Cited by 57
Borsarelli, C. D., Falomir‐Lockhart, L. J., Ostatná, V., Fauerbach, J. A., Hsiao, H., Urlaub, H., Paleček, E., Jares-Erijman, E. A., & Jovin, T. M. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.06.035 · Cited by 55
“5 kDa) negatively charged, natively disordered protein lacking a distinct secondary structure when free in solution [3], although recent reports suggest that aS may adopt a distinct conformation in vivo [6,7].”
BackgroundGarten, M., Prévost, C., Cadart, C., Gautier, R., Bousset, L., Melki, R., Bassereau, P. M., & Vanni, S. (2015) · Physical Chemistry Chemical Physics · doi:10.1039/c5cp00244c · Cited by 52
Blennow, K., Biscetti, L., Eusebi, P., & Parnetti, L. (2016) · Movement Disorders · doi:10.1002/mds.26656 · Cited by 61
“a-syn undergoes several posttranslational modifications, including phosphorylation,(58) ubiquitination,(59) nitration,(60) sumoylation,(61) glycosylation,(62) truncation,(63) and acetylation.(64) These posttranslational modifications might play some role in PD pathogenesis by promoting a-syn aggregation and toxicity (…”
BackgroundWerner‐Allen, J. W., DuMond, J. F., Levine, R. L., & Bax, A. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201600277 · Cited by 56
Alpha-synuclein, Proteotoxicity and Parkinson's Disease: Search for Neuroprotective Therapy
Ganguly, U., Chakrabarti, S. S., Kaur, U., Mukherjee, A., & Chakrabarti, S. (2018) · Current Neuropharmacology · doi:10.2174/1570159x15666171129100944 · Cited by 58
“Some studies have indicated that α-synuclein under physiological conditions in neural and non-neural tissues exists as partially α-helical tetramers with minor amounts of higher oligomeric forms in equilibrium with monomeric forms; while others have shown that it exists primarily in unfolded monomeric forms [17-19].”
BackgroundPang, C. C.-C., Kiecker, C. M., O'Brien, J. T., Noble, W. J., & Chang, R. C. (2018) · The Neuroscientist · doi:10.1177/1073858418778747 · Cited by 60
Vesicle trafficking and lipid metabolism in synucleinopathy
Fanning, S., Selkoe, D. J., & Dettmer, U. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02177-z · Cited by 56
Self-citationMembrane-induced folding of the plant-stress protein Lti30.
Eriksson, S. K., Eremina, N., Barth, A., Danielsson, J., & Harryson, P. (2016) · PLANT PHYSIOLOGY · doi:10.1104/pp.15.01531 · Cited by 57
“, 2013), and protein-protein interaction (Sinha and Smith-Gill, 2002; Müller et al., 2003; Bartels et al., 2011).”
BackgroundTreating Parkinson’s Disease with Antibodies: Previous Studies and Future Directions
Castonguay, A.-M., Gravel, C., & Lévesque, M. (2020) · Journal of Parkinson s Disease · doi:10.3233/jpd-202221 · Cited by 55
“Studies have suggested that it also exists as a stable tetramer in the cytoplasm, and it is likely that both forms are present in physiological conditions [37, 38].”
BackgroundChen, J., Zaer, S., Drori, P., Zamel, J., Joron, K., Kalisman, N., Lerner, E., & Dokholyan, N. V. (2021) · Structure · doi:10.1016/j.str.2021.05.002 · Cited by 55
Khan, A. N., & Khan, R. H. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.11.031 · Cited by 58
Conformational heterogeneity of α -synuclein in membrane
Vermaas, J. V., & Tajkhorshid, E. (2014) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2014.08.012 · Cited by 53
“Some have suggested that only αS aggregates bind tomembranes [26], or that αS binds as a tetramer [32].”
Microsecond folding experiments and simulations: a match is made
Prigozhin, M. B., & Gruebele, M. (2013) · Physical Chemistry Chemical Physics · doi:10.1039/c3cp43992e · Cited by 56
Preparation and Characterization of Stable α-Synuclein Lipoprotein Particles
Eichmann, C., Campioni, S., Kowal, J., Maslennikov, I., Gerez, J., Liu, X., Verasdonck, J., Nespovitaya, N., Choe, S., Meier, B. H., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.707968 · Cited by 55
Zhang, Y., Wang, Y., Liu, Y., Wei, G., Ding, F., & Sun, Y. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00531 · Cited by 54
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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