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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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“Notably, membrane lipid binding is necessary for the unstructured protein to obtain an α-helix-rich structure [25], which governs α-Syn’s oligomerization in soluble oligomers [23, 24, 29].”
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Self-citationRationally designed helical peptidomimetics disrupt α-synuclein fibrillation
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“In addition, endogenous αSyn is also reported to form α-helical tetramers in cell cultures and brain tissue that are resistant to pathogenic aggregation (Bartels et al., 2011; Wang et al., 2011).”
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“Endogenous α-syn exists as a helical tetramer of 58 kDa in neuronal and nonneuronal cells under non-denaturing conditions and its destabilization leads to its aggregation (Bartels et al., 2011).”
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Parkinson’s Disease and the Gut: Future Perspectives for Early Diagnosis
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“Physiologically, αS most commonly occurs in the form of stable unfolded monomers (Eliezer et al., 2001) or folded tetramers (Bartels et al., 2011).”
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“In its native state, α -syn is an unstructured monomer that can adopt an α -helical conformation upon interacting with phospholipids (Bartels et al., 2011; Wang et al., 2011; Burr´e et al., 2013; Breydo et al., 2012; Theillet et al., 2016; Rovere et al., 2018; Galvagnion et al., 2015; Weinreb et…”
A sensitive assay reveals structural requirements for α-synuclein fibril growth
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Isolation of recombinant tetrameric N-acetylated α-synuclein
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“α-synuclein is a soluble and unfolded protein that forms tetramers under physiological conditions in the brain (Figure 1 [18,19]).”
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Structural and dynamic insights into α-synuclein dimer conformations
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“α-Synuclein is a 140-amino acid pre-synaptic protein that exists physiologically as either an intrinsically disordered monomer or an α-helical tetramer [3, 18].”
BackgroundJuxtanodin is an intrinsically disordered F-actin-binding protein
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Screening methods for identifying pharmacological chaperones
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The localization of α-synuclein in the process of differentiation of human erythroid cells
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“In this context, some studies have shown that α Syn may also exist as a helically folded tetramer or multimer in healthy cells [66], which appears to be more stable and resistant to aggregation, suggesting a potential protective role in healthy neurons [67].”
McDowall, J., Ntai, I., Hake, J., Whitley, P. R., Mason, J. M., Pudney, C. R., & Brown, D. R. (2017) · Biochemistry · doi:10.1021/acs.biochem.7b00257 · Cited by 26
Re-designing the α-synuclein tetramer
Xu, L., Bhattacharya, S., & Thompson, D. (2018) · Chemical Communications · doi:10.1039/c8cc04054k · Cited by 24
On the ubiquity of helical α-synuclein tetramers
Xu, L., Bhattacharya, S., & Thompson, D. (2019) · Physical Chemistry Chemical Physics · doi:10.1039/c9cp02464f · Cited by 23
Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells
Lorentzon, E., Horváth, I., Kumar, R., Rodrigues, J. I., Tamás, M. J., & Wittung-Stafshede, P. E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111455 · Cited by 24
“The αSyn variant used in this study is the biologically relevant N-terminally acetylated αSyn (Ac αSyn), as acetylation has been reported to be a general posttranslational modification to the protein [44], which also occurs naturally when expressed in yeast [45].”
BackgroundMethodPassive Immunization in Alpha-Synuclein Preclinical Animal Models
Folke, J., Ferreira, N., Brudek, T., Borghammer, P., & Berge, N. V. D. (2022) · Biomolecules · doi:10.3390/biom12020168 · Cited by 23
“αsyn is likely to exist both as unstructured monomers and helical oligomers [34,35].”
BackgroundLow dose DMSO treatment induces oligomerization and accelerates aggregation of α-synuclein
Reimer, L., Haikal, C., Gram, H., Theologidis, V., Kovács, G. E., Ruesink, H., Baun, A. M., Nielsen, J., Otzen, D. E., Li, J., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-07706-2 · Cited by 22
“chemical cross-linkers used to stabilize tetrameric α-syn [3, 4, 12].”
BackgroundMolecular Tweezers: Supramolecular Hosts with Broad-Spectrum Biological Applications
Shahpasand‐Kroner, H., Siddique, I. A., Malik, R., Linares, G. R., Ivanova, M. I., Ichida, J. K., Weil, T., Münch, J., Sánchez‐García, E., Klärner, F., et al. (2022) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000654 · Cited by 25
Ahanger, I. A., & Dar, T. A. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102538 · Cited by 26
Roodveldt, C., Andersson, A., Genst, E. D., Labrador‐Garrido, A., Buell, A. K., Dobson, C. M., Tartaglia, G. G., & Vendruscolo, M. (2012) · Biochemistry · doi:10.1021/bi300558q · Cited by 24
Kumar, S., Birol, M., & Miranker, A. D. (2016) · Chemical Communications · doi:10.1039/c6cc01248e · Cited by 24
Delic, V., Griffin, J. W. D., Zivkovic, S., Zhang, Y., Phan, T.-A., Gong, H., Chaput, D., Reynes, C., Dinh, V. B., Cruz, J., et al. (2017) · NeuroMolecular Medicine · doi:10.1007/s12017-017-8448-8 · Cited by 25
“…Leads to Its Oligomerization The human brain contains both monomers and other higher order multimeric conformers of a-syn such as dimers, trimers, tetramers, and high molecular weight oligomers (Gould et al. 2014), with the tetrameric form of a-syn being very stable (Bartels et al. 2011).”
BackgroundKumar, V. B., Hsu, F., Lakshmi, V. M., Gillespie, K. N., & Burke, W. J. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.12.027 · Cited by 24
Vertebrate food products as a potential source of prion-like α-synuclein
Killinger, B. A., & Labrie, V. (2017) · npj Parkinson s Disease · doi:10.1038/s41531-017-0035-z · Cited by 23
“, dimer, tetramer, octamer) that are likely important for its endogenous functions, such as intracellular vesicular trafficking.(10,11) α-Synuclein can also form progressively massive insoluble amyloid fibrils in vitro that consist of hundreds of α-synuclein proteins in a stable β-sheet conformation.”
BackgroundToxic properties of microsome-associated alpha-synuclein species in mouse primary neurons
Colla, E., Panattoni, G., Ricci, A., Rizzi, C., Rota, L., Carucci, N. M., Valvano, V., Gobbo, F., Capsoni, S., Lee, M. K., et al. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.12.004 · Cited by 23
“…al., 2013; Chandra et al., 2003; Fauvet et al., 2012; Theillet et al., 2016; Weinreb et al., 1996), although lately these data have been questioned (Bartels et al., 2011; Dettmer et al., 2015; Wang et al., 2011)] to an oligomer-type of structure and the transition to an insoluble β-sheet rich…”
D’Onofrio, M., Munari, F., & Assfalg, M. (2020) · Molecules · doi:10.3390/molecules25235625 · Cited by 23
“Environmental changes, binding events and other stimuli may promote the transition from the soluble monomeric and small oligomeric states to higher-level oligomers, fibrils (highly ordered supramolecular nanostructures) and amorphous aggregates [12,15,19,20].”
BackgroundEffects of Excess Brain-Derived Human α-Synuclein on Synaptic Vesicle Trafficking
Román‐Vendrell, C., Medeiros, A. T., Sanderson, J. B., Jiang, H., Bartels, T., & Morgan, J. R. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.639414 · Cited by 22
“However, recent studies have provided strong evidence that native, physiological α-synuclein exists as helically folded multimers, principally as tetramers and related multimers (Bartels et al., 2011; Wang et al., 2011; Dettmer et al., 2013; Xu et al., 2019).”
BackgroundResultInfluentialSelf-citationWang, Q., Yao, S., Yang, Z.-X., Zhou, C., Zhang, Y., Zhang, L., Zhang, L., Li, J., Xu, Z.-J., Zhu, W.-L., et al. (2023) · Acta Pharmacologica Sinica · doi:10.1038/s41401-022-01039-6 · Cited by 23
“α-Synuclein, a helically folded tetramer, can physiologically resist aggregation [29].”
BackgroundNMR Structure of Calmodulin Complexed to an N-Terminally Acetylated α-Synuclein Peptide
Gruschus, J. M., Yap, T. L., & Lee, J. C. (2013) · Biophysical Journal · doi:10.1016/j.bpj.2012.11.330 · Cited by 23
A Focus on the Beneficial Effects of Alpha Synuclein and a Re-Appraisal of Synucleinopathies
Ryskalin, L., Busceti, C. L., Limanaqi, F., Biagioni, F., Gambardella, S., & Fornai, F. (2017) · Current Protein and Peptide Science · doi:10.2174/1389203718666171117110028 · Cited by 23
“In contrast, in 2011 Bartels and coworkers [164] reported that endogenous α-syn occurs mainly as a stably folded tetramer of about 58 kDa.”
BackgroundParsons, C. G. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.08.027 · Cited by 22
“As such, there is still a huge unmet medical need for new neuroprotective drugs for the treatment of PD. α-synuclein is also a physiologically important protein (Bartels et al., 2011; Bisaglia et al., 2009).”
BackgroundIn-cell NMR: from metabolites to macromolecules
Lippens, G. M., Cahoreau, E., Millard, P., Charlier, C., Lopez, J. M., Hanoulle, X., & Portais, J. (2018) · The Analyst · doi:10.1039/c7an01635b · Cited by 25
Chetty, D., Abrahams, S., van Coller, R., Carr, J. A., Kenyon, C. P., & Bardien, S. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15324 · Cited by 22
Interplay between α-synuclein and parkin genes: Insights of Parkinson’s disease
Sharma, K., Chib, S., Gupta, A., Singh, R., & Chalotra, R. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09520-7 · Cited by 22
“However, it has been shown that α-syn exist as unfolded monomer which binds to lipid vesicles to form α helical secondary structure [ 14 ].”
Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation
Zhao, C., Tu, J., Wang, C., Liu, W., Gu, J., Yin, Y., Zhang, S., Li, D., Diao, J., Zhu, Z., et al. (2024) · National Science Review · doi:10.1093/nsr/nwae182 · Cited by 23
“Despite its high propensity to aggregate, native α -syn is highly abundant in neurons ( ∼ 1% of all proteins) and resists aggregation in normal intracellular environments [5 –8 ].”
BackgroundInvestigational α-synuclein aggregation inhibitors: hope for Parkinson’s disease
Török, N., Majláth, Z., Szalárdy, L., & Vécsei, L. (2016) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2016.1237501 · Cited by 23
Je, G., Croop, B., Basu, S., Tang, J., Han, K. Y., & Kim, Y.-S. (2017) · Analytical Chemistry · doi:10.1021/acs.analchem.7b04335 · Cited by 21
Yeboah, F., Kim, T., Bill, A., & Dettmer, U. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104543 · Cited by 22
Intrinsic disorder in the kinesin superfamily
Seeger, M. A., & Rice, S. E. (2012) · Biophysical Reviews · doi:10.1007/s12551-012-0096-5 · Cited by 22
“…study in which α-synuclein was carefully purified from mammalian cells under non-denaturing conditions—rather than expressed and purified from bacterial lysates—showed that α-synuclein actually exists as a folded α-helical tetramer in both its apo and lipid-bound states (Bartels et al. 2011).”
Renella, R., Schlehe, J. S., Selkoe, D. J., Williams, D. A., & LaVoie, M. J. (2014) · American Journal of Hematology · doi:10.1002/ajh.23796 · Cited by 23
Self-citationLorentzon, E., Kumar, R., Horváth, I., & Wittung-Stafshede, P. E. (2020) · BioMetals · doi:10.1007/s10534-020-00234-4 · Cited by 21
“As it is now established that aSyn is acetylated at the N-terminal amino group in vivo (Bartels et al. 2011), we here focused on wild-type (WT) and Ala53Thr (A53T; early onset PD-causing mutation) (Polymeropoulos et al.”
BackgroundChopra, G., Shabir, S., Yousuf, S., Kauts, S., Bhat, S. A., Mir, A. H., & Singh, M. P. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03042-8 · Cited by 24
Effect of Surfactant Hydrophobicity on the Pathway for Unfolding of Ubiquitin
Shaw, B. F., Schneider, G. F., & Whitesides, G. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja3079863 · Cited by 21
High‐density lipoprotein‐like particle formation of Synuclein variants
Eichmann, C., Kumari, P., & Riek, R. (2016) · FEBS Letters · doi:10.1002/1873-3468.12543 · Cited by 21
Manecka, D.-L., Vanderperre, B., Fon, E. A., & Durcan, T. M. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00311 · Cited by 21
“Under physiological conditions, α-syn is soluble and intrinsically disordered, or can adopt an N-terminal α-helix conformation with high affinity for biological membranes (Bartels et al., 2011).”
BackgroundMPTAC Determines APP Fragmentation via Sensing Sulfur Amino Acid Catabolism
Suganuma, T., Swanson, S. K., Gogol, M., Garrett, T. J., Conkright-Fincham, J., Florens, L. A., Washburn, M. P., & Workman, J. L. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.013 · Cited by 21
Gentile, I., Garro, H. A., Delgado‐Ocaña, S., González, N., Strohäker, T., Schibich, D., Quintanar, L., Sambrotta, L., Zweckstetter, M., Griesinger, C., et al. (2018) · Metallomics · doi:10.1039/c8mt00232k · Cited by 21
C-Terminal Cu II Coordination to α-Synuclein Enhances Aggregation
Abeyawardhane, D. L., Heitger, D. R., Fernández, R. D., Forney, A. K., & Lucas, H. R. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00448 · Cited by 22
Landeck, N., Strathearn, K. E., Ysselstein, D., Buck, K., Dutta, S., Banerjee, S., Lv, Z., Hulleman, J. D., Hindupur, J., Lin, L.-K., et al. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00380-w · Cited by 19
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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