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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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“Unauthenticated | 150.108.161.71 Download Date | 1/21/13 7:35 PM α -Syn aggregation α -Syn is thought of as an intrinsically unfolded protein, but recent studies have demonstrated that it may occur natively as an α -helical tetramer (Bartels et al. , 2011 ; Wang et al. , 2011 ).”
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“α-synuclein exists in neurons as monomeric species in equilibration with ordered tetramers, and in both forms the protein conformation is likely dependent upon association with lipid membranes [1,14,15].”
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“Although it is widely believed that α-syn exists mainly as monomer, studies have also shown that endogenous α-syn can form tetramers [27, 28], which comprise an alpha-helical secondary structure and show little tendency to form aggregates [29].”
BackgroundDifferential Activation of the ER Stress Factor XBP1 by Oligomeric Assemblies
Castillo‐Carranza, D. L., Zhang, Y., Guerrero‐Munoz, M. J., Kayed, R., Rincón-Limas, D. E., & Fernández-Fúnez, P. (2012) · Neurochemical Research · doi:10.1007/s11064-012-0780-7 · Cited by 51
“a-Syn is a soluble presynaptic protein thought to exist in an unstructured state in solution, although a helical tetramer has recently been proposed to exist in physiological conditions [4].”
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“Previous work suggests that naturally occurring high-MW aSYN species have a physiological role (60) and targeted mutagenesis of SNCA prevents the formation of aggregation-prone monomers in mice (61, 62).”
Effects of Mutations and Post-Translational Modifications on α-Synuclein In Vitro Aggregation
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“26 However, there is controversy regarding whether α-syn may exhibit a tet-rameric structure in the brain.”
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“Moreover, it has also been posited that physiologically, a -syn may function as a multi-meric protein (20 – 23). a -syn ’ s cellular localization and function are somewhat diverse, as it resides in the cytoplasm physiologically but has an af fi nity toward membranes (24).”
Backgroundα-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges
Arias-Carrión, Ó., Guerra‐Crespo, M., Padilla-Godínez, F. J., Soto-Rojas, L. O., & Manjarrez, E. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26115405 · Cited by 51
“However, although studies suggest that these assemblies may be physiologically relevant—potentially regulating neurotransmitter release, glutamatergic receptor activity, and synaptic function [33–37]—their prevalence and functional significance remain debated [17,38].”
α-Synuclein Levels in Blood Plasma from LRRK2 Mutation Carriers
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“Intriguingly, recent results of two independent studies have postulated that the native a-synuclein structure is not unfolded monomers but rather an a-helically folded tetramer that is stable and resistant to self-aggregation [44,45].”
BackgroundAlpha Synuclein in Parkinson’s Disease
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“In this study, we found that female sex increases S T:M ratio, as determined by intact-cell crosslinking, which not only measures soluble S forms but also reflects aggregate-resistant S forms (Bartels et al., 2011).”
BackgroundInfluentialα‐Synuclein in blood cells differentiates Parkinson’s disease from healthy controls
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Ellagic Acid Inhibits α-Synuclein Aggregation at Multiple Stages and Reduces Its Cytotoxicity
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“There is evidence of an endogenous metastable non-toxic a-syn multimer that resists progressive aggregation (Bartels et al. 2011); however, the means by which fibrils and endogenous multimers might interact is unclear.”
BackgroundAvidity within the N‐terminal anchor drives α‐synuclein membrane interaction and insertion
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“Using SDS micelles, two antiparallel helices in aSN, H1 (3-37) and H2 (45-92), were assigned15 and similar helix break observations22 or different helical binding modes13 were reported by others.”
Backgroundα-Synuclein, Lrrk2 and Their Interplay In Parkinson‘s Disease
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“helical structures and is more resistant to aggregation [13].”
BackgroundSarafian, T. A., Ryan, C. M., Souda, P., Masliah, E., Kar, U. K., Vinters, H. V., Mathern, G. W., Faull, K. F., Whitelegge, J. P., & Watson, J. B. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063557 · Cited by 44
“Interestingly there are reports suggesting that a soluble form of a-synuclein similar in size (, 60 kDa) may exist as an a-helical tetramer and may need to destabilize to form disordered monomers prior to forming more toxic soluble amyloid-like oligomers and pre-fibrils [43,44,49].”
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Alpha-synuclein: relating metals to structure, function and inhibition
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A small-angle X-ray scattering study of alpha-synuclein from human red blood cells
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“The aSyn protein is intrinsically disordered, existing predominantly as a monomer (7), although tetrameric conformations could exist in a dynamic equilibrium (8).”
BackgroundPortrait of blood-derived extracellular vesicles in patients with Parkinson’s disease
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Natural compound safranal driven inhibition and dis-aggregation of α-synuclein fibrils
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Distinct phases of free α‐synuclein—A Monte Carlo study
Jónsson, S. Æ., Mohanty, S., & Irbäck, A. (2012) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.24107 · Cited by 43
Dettmer, U. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00623 · Cited by 43
Vinueza‐Gavilanes, R., Íñigo-Marco, I., Larrea, L., Lasa, M., Carte, B., Santamaría, E., Fernández‐Irigoyen, J., Bugallo, R., Aragón, T., Aldabe, R., et al. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104781 · Cited by 44
Cryo-EM structure of alpha-synuclein fibrils amplified by PMCA from PD and MSA patient brainsPreprint
Burger, D., Fenyi, A., Bousset, L., Stahlberg, H., & Melki, R. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.08.451588 · Cited by 43
“Upon interaction with acidic phospholipids, seven imperfect amino-terminal repeats, consisting of 11 amino acid long stretches centered on the consensus KTKEGV, adopt an alpha-helical conformation (Bartels et al., 2011; Chandra et al., 2003; Ulmer et al., 2005).”
BackgroundTwo-step screening method to identify α-synuclein aggregation inhibitors for Parkinson’s disease
Hideshima, M., Kimura, Y., Aguirre, C., Kakuda, K., Takeuchi, T., Choong, C., Doi, J., Nabekura, K., Yamaguchi, K., Nakajima, K., et al. (2022) · Scientific Reports · doi:10.1038/s41598-021-04131-9 · Cited by 42
Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?
Brembati, V., Faustini, G., Longhena, F., & Bellucci, A. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1197853 · Cited by 43
“Indeed, recent findings indicate that all the in vivo detectable α-Syn is post-translationally modified by an acetyl group attached to the amino group of the first N-terminal amino acid (Anderson et al., 2006; Bartels et al., 2011; Ohrfelt et al., 2011).”
BackgroundPosttranslational Modifications and Clearing of α-Synuclein Aggregates in Yeast
Popova, B., Kleinknecht, A., & Braus, G. H. (2015) · Biomolecules · doi:10.3390/biom5020617 · Cited by 43
Structural studies on the mechanism of protein aggregation in age related neurodegenerative diseases
Eftekharzadeh, B., Hyman, B. T., & Wegmann, S. (2016) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.03.001 · Cited by 44
Heme Stabilization of α-Synuclein Oligomers during Amyloid Fibril Formation
Hayden, E. Y., Kaur, P., Williams, T. L., Matsui, H., Yeh, S., & Rousseau, D. L. (2015) · Biochemistry · doi:10.1021/acs.biochem.5b00280 · Cited by 42
Horizontal Transmission of Cytosolic Sup35 Prions by Extracellular Vesicles
Liu, S., Hossinger, A., Hofmann, J. P., Denner, P., & Vorberg, I. M. (2016) · mBio · doi:10.1128/mbio.00915-16 · Cited by 42
“used successfully to preserve the assembled state of the putative -synuclein oligomers (41, 42).”
Motyl, J. A., Wencel, P. L., Cieślik, M., Strosznajder, R. P., & Strosznajder, J. B. (2017) · Molecular Neurobiology · doi:10.1007/s12035-016-0317-1 · Cited by 42
“The data of Bartels et al. 2011 [8] indicate that ASN occurs physiologically as a helically folded tetramer that is resistant to aggregation.”
BackgroundMethodA critical review of the prion hypothesis of human synucleinopathies
Tamgüney, G., & Korczyn, A. D. (2017) · Cell and Tissue Research · doi:10.1007/s00441-017-2712-y · Cited by 42
“While it is thought that under physiologic conditionsα-syn is unfolded with little or no secondary structure, some recent studies suggest that nativeα-synmay form a tetramer (Bartels et al. 2011; Weinreb et al. 1996).”
Backgroundα-Synuclein Dimers Impair Vesicle Fission during Clathrin-Mediated Synaptic Vesicle Recycling
Medeiros, A. T., Soll, L. G., Tessari, I., Bubacco, L., & Morgan, J. R. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00388 · Cited by 43
“…useful for determining the effects of other molecular species of α-synuclein, including tetramers that have recently been described as the native form of the protein (Bartels et al., 2011; Dettmer et al., 2013, 2015a), though this interpretation remains somewhat controversial (Burré et al., 2013).”
BackgroundE46K-like α-synuclein mutants increase lipid interactions and disrupt membrane selectivity
Rovere, M., Powers, A. E., Jiang, H., Pitino, J. C., Fonseca‐Ornelas, L., Patel, D. S., Achille, A., Langen, R., Varkey, J., & Bartels, T. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.006551 · Cited by 42
“In addition, such mutants have been shown to markedly decrease the ratio between aggregation-resistant Syn tetramers (29) and aggregation-prone monomers, whose imbalance has been proposed as one of the molecular mechanisms underlying disease inception (28, 30).”
Self-citationLipid-Binding Proteins in Brain Health and Disease
Corraliza-Gómez, M., Sánchez, D., & Ganfornina, M. D. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01152 · Cited by 43
Fernández‐Espejo, E., García-Moreno, J., de Pablos, Á. M., & Chacón, J. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5250 · Cited by 42
“The protein aSyn was detected in both serum and CSF, where levels were found to be lower in patients than controls (8), and as a tetramer (*56 kDa), its actual physiological shape (1).”
Rodger, A. T., ALNasser, M. N., & Carter, W. G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241311022 · Cited by 41
“α-syn can shift between multiple protein conformations due to its structural flexibility, moving from monomers to oligomers (soluble forms) such as tetramers [16,17] and then”
BackgroundCordeiro, Y., Macedo, B., Silva, J. L., & Gomes, M. P. B. (2014) · Biophysical Reviews · doi:10.1007/s12551-013-0132-0 · Cited by 40
α-Synuclein nonhuman primate models of Parkinson’s disease
Marmion, D. J., & Kordower, J. H. (2017) · Journal of Neural Transmission · doi:10.1007/s00702-017-1720-0 · Cited by 44
“2001), as well as the formation of its alpha-helical secondary structure (Bartels et al. 2011).”
BackgroundKhair, S. B. A., Dhanushkodi, N. R., Ardah, M. T., Chen, W., Yang, Y., & Haque, M. E. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00081 · Cited by 41
“…α-syn is a presynaptic protein encoded by the gene SNCA, mutations of which lead to formation of insoluble species of the protein; which in its native state is monomeric and soluble. α-Syn is also reported to exist as helically folded tetramer that resist aggregation (Bartels et al., 2011).”
BackgroundFoods with Potential Prooxidant and Antioxidant Effects Involved in Parkinson’s Disease
Miranda‐Díaz, A. G., García-Sánchez, A., & Cardona-Muñóz, E. G. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/6281454 · Cited by 46
“A recent study suggests that α-synuclein monomers and tetramers are the physiological forms, while oligomers and fibrils are the pathogenic forms [7].”
BackgroundGlajch, K. E., Moors, T. E., Chen, Y., Bechade, P. A., Nam, A. Y., Rajsombath, M. M., McCaffery, T. D., Dettmer, U., Weihofen, A., Hirst, W. D., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2103425118 · Cited by 43
“The 3K mutation shifts the normally aggregation-resistant αS tetramers (12) to increased levels of monomers that then cluster with vesicle membranes and form sizeable aggregates, thereby producing multiple PD-like motor phenotypes by the age of 6 mo (23).”
BackgroundSelf-citationXin, W., Emadi, S., Williams, S. M., Liu, Q., Schulz, P., He, P., Alam, N. B., Wu, J., & Sierks, M. R. (2015) · Biomolecules · doi:10.3390/biom5031634 · Cited by 40
α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies
Abdelkarim, H., Marshall, M. S., Scesa, G., Smith, R. A., Rue, E. A., Marshall, J. N., Elackattu, V., Stoskute, M., Issa, Y., Santos, M. B., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-30808-9 · Cited by 39
A cullin-RING ubiquitin ligase targets exogenous α-synuclein and inhibits Lewy body–like pathology
Gerez, J., Prymaczok, N. C., Rockenstein, E. M., Herrmann, U., Schwarz, P., Adame, A., Enchev, R. I., Courthéoux, T., Boersema, P. J., Riek, R., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aau6722 · Cited by 39
Sanderson, J. B., De, S., Jiang, H., Rovere, M., Jin, M., Zaccagnini, L., Watson, A. H., de Boni, L., Lagomarsino, V. N., Young‐Pearse, T. L., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa010 · Cited by 41
“Thus, it is possible that in the pathological state, more aSyn is in a disordered, cytosolic state that is more prone to aggregation than the multimeric state (Bartels et al., 2011).”
BackgroundSelf-citationDetection and Assessment of α-Synuclein Oligomers in the Urine of Parkinson’s Disease Patients
Nam, D., Lee, J., Lee, M., Kim, J., Seol, W., Son, I., & Ho, D. H. (2020) · Journal of Parkinson s Disease · doi:10.3233/jpd-201983 · Cited by 42
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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