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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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“Native a-syn tetramers enriched in alpha-helical structure were also reported after non-denaturing purification from mammalian cells (Bartels et al. 2011).”
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DisProt: intrinsic protein disorder annotation in 2020
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“For example, it was recently applied to study Parkinson’s disease protein -synuclein (DisProt DP00070), once suggested to have folded, oligomeric structure in cells (11).”
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“1B, fifth and sixth panels), consistent with our previous Syn cross-linking results using DSS (1).”
BackgroundMethodResultInfluentialSelf-citationImpact of N-Terminal Acetylation of α-Synuclein on Its Random Coil and Lipid Binding Properties
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microRNAs in Parkinson’s Disease: From Pathogenesis to Novel Diagnostic and Therapeutic Approaches
Leggio, L., Vivarelli, S., L’Episcopo, F., Tirolo, C., Caniglia, S., Testa, N., Marchetti, B., & Iraci, N. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122698 · Cited by 218
“α-SYN is an unstructured soluble protein, forming stably folded tetramers [75].”
BackgroundZhang, J., Li, X., & Li, J. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00381 · Cited by 225
“They further showed that very few native human α-synuclein tetramers form aggregation, whereas recombinantly expressed monomers readily aggregated into amyloid-like fibrils in vitro (Bartels et al., 2011).”
BackgroundMechanism of Membrane Interaction and Disruption by α-Synuclein
Reynolds, N. P., Soragni, A., Rabe, M., Verdes, D., Liverani, E., Handschin, S., Riek, R., & Seeger, S. (2011) · Journal of the American Chemical Society · doi:10.1021/ja2029848 · Cited by 215
Seeking a Mechanism for the Toxicity of Oligomeric α-Synuclein
Hall‐Roberts, H., & Brown, D. R. (2015) · Biomolecules · doi:10.3390/biom5020282 · Cited by 222
Parkinson disease therapy: current strategies and future research priorities
Stocchi, F., Bravi, D., Emmi, A., & Antonini, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-01034-x · Cited by 247
“neuronal soma (Lewy bodies) and, through immunohistochemical staining, also in axons and dendrites 48–50 (Lewy neurites).”
Cerebrospinal fluid biomarkers in Parkinson disease
Parnetti, L., Castrioto, A., Chiasserini, D., Persichetti, E., Tambasco, N., El-Agnaf, O., & Calabresi, P. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.10 · Cited by 209
Chung, S. Y., Kishinevsky, S., Mazzulli, J. R., Graziotto, J. J., Mrejeru, A., Mosharov, E. V., Puspita, L., Valiulahi, P., Sulzer, D., Milner, T. A., et al. (2016) · Stem Cell Reports · doi:10.1016/j.stemcr.2016.08.012 · Cited by 204
“Studies point toward the oligomeric and fibrillary a-synuclein species as being the toxic and pathogenic forms present in Parkinson’s disease while the monomeric or tetrameric a-synuclein are likely physiological forms (Bartels et al., 2011; Marques and Outeiro, 2012).”
BackgroundVidović, M., & Rikalović, M. (2022) · Cells · doi:10.3390/cells11111732 · Cited by 214
“An extended α-Syn helical form can form homotetramers that might be more resistant to aggregation [71,72].”
BackgroundPenchala, S., Connelly, S., Wang, Y., Park, M. S., Zhao, L., Baranczak, A., Rappley, I., Vogel, H. S., Liedtke, M., Witteles, R. M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1300761110 · Cited by 203
“It has been proposed that, analogous to TTR, small-molecule stabilizers of the physiological tetramer of α-synuclein could reduce its pathogenicity in Parkinson disease (39).”
BackgroundCardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein
Ryan, T. L., Bamm, V. V., Stykel, M. G., Coackley, C. L., Humphries, K. M., Jamieson-Williams, R., Ambasudhan, R., Mosser, D. D., Lipton, S. A., Harauz, G., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03241-9 · Cited by 212
Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson’s Disease-like Dementia
Ejlerskov, P., Hultberg, J. G., Wang, J., Carlsson, R., Ambjørn, M., Kuss, M., Liu, Y., Porcu, G., Kolkova, K., Friis Rundsten, C., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.069 · Cited by 211
“…are neurotoxic (Rockenstein et al., 2014), a -syn tetramers are suggested to be the normal aggregation resistant conformation of the protein (Bartels et al., 2011; Wang et al., 2011), possibly explaining the tetramer abundance in Ifnb +/+ mice. pSer129-a -syn, which is prone to form…”
Autophagic failure promotes the exocytosis and intercellular transfer of α-synuclein
Lee, H.-J., Cho, E.-D., Lee, K., Kim, J., Cho, S., & Lee, S. (2013) · Experimental & Molecular Medicine · doi:10.1038/emm.2013.45 · Cited by 204
Monomeric Synucleins Generate Membrane Curvature
Westphal, C. H., & Chandra, S. S. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.418871 · Cited by 202
“While the tetrameric form of -synuclein also binds acidic lipid membranes (16), it is not known if binding is membrane curvature-dependent.”
BackgroundInfluentialKang, L., Moriarty, G. M., Woods, L. A., Ashcroft, A. E., Radford, S. E., & Baum, J. (2012) · Protein Science · doi:10.1002/pro.2088 · Cited by 202
“in which asyn was isolated from red blood cells, as well as neuronal and non-neuronal cell lines, reported that in its physiological form, asyn exists as a helical tetramer that is resistant to amyloid formation, and has a mass corresponding to the sole modification of the monomer by an acetyl group.(3) Shortly therea…”
BackgroundDovonou, A., Bolduc, C., Linan, V. S., Gora, C., Peralta, M. R., & Lévesque, M. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00368-8 · Cited by 218
“Usually clustering into monomers and tetramers [239, 240], α-syn assembles into higher-order structures under pathological conditions.”
BackgroundBourdenx, M., Koulakiotis, N. S., Sanoudou, D., Bézard, E., Dehay, B., & Tsarbopoulos, A. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.07.003 · Cited by 202
“However, recent evidence has suggested it may form a folded tetramer with a a-helical secondary structure in some cell types (Bartels et al., 2011; Dettmer et al., 2013; Wang et al., 2011).”
BackgroundDikiy, I., & Eliezer, D. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.512459 · Cited by 194
“acetylation (24, 25) or by an N-terminal fusion-protein remnant (26).”
BackgroundA longitudinal study on α-synuclein in blood plasma as a biomarker for Parkinson's disease
Foulds, P. G., Diggle, P. J., Mitchell, J. D., Parker, A., Hasegawa, M., Masuda‐Suzukake, M., Mann, D. M. A., & Allsop, D. (2013) · Scientific Reports · doi:10.1038/srep02540 · Cited by 191
Curcumin Prevents Aggregation in α-Synuclein by Increasing Reconfiguration Rate
Ahmad, B., & Lapidus, L. J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.325548 · Cited by 185
“Although -synuclein is commonly thought of as intrinsically disordered, a recent report demonstrated that, in human cells, it exists in a helical tetramer that does not easily aggregate (2).”
BackgroundZhang, Y., Caulfield, T. R., Xu, Y., Gendron, T. F., Hubbard, J., Stetler, C. T., Sasaguri, H., Whitelaw, E. C., Cai, S., Lee, C. W., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt166 · Cited by 187
“Consistent with previous findings (24,29), DSG treatment also stabilized DJ-1 homodimers, the native form of DJ-1 in cells (26,30,31), validating our experimental conditions were sufficient to stabilize native protein structures.”
ResultImpaired intracellular trafficking defines early Parkinson's disease
Hunn, B. H. M., Cragg, S. J., Bolam, J. P., Spillantini, M., & Wade‐Martins, R. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2014.12.009 · Cited by 198
Metal ions as modulators of protein conformation and misfolding in neurodegeneration
Leal, S. S., Botelho, H. M., & Gomes, C. M. (2012) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2012.04.004 · Cited by 187
Sorrentino, Z. A., Giasson, B. I., & Chakrabarty, P. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-01977-2 · Cited by 179
“αSyn has been shown to exist as an inherently disordered monomer [161] or more controversially, as tetramers [15].”
Genetics and genomics of Parkinson’s disease
Lin, M. K., & Farrer, M. J. (2014) · Genome Medicine · doi:10.1186/gm566 · Cited by 183
GBA1 deficiency negatively affects physiological α-synuclein tetramers and related multimers
Kim, S., Yun, S. P., Lee, S., Umanah, G. K. E., Bandaru, V. V. R., Yin, X., Rhee, P., Karuppagounder, S. S., Kwon, S., Lee, H., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700465115 · Cited by 180
“Recent studies indicate that α-syn physiologically exists as a folded helical tetramer that resists aggregation (9, 10).”
BackgroundInfluentialDettmer, U., Newman, A. J., von Saucken, V. E., Bartels, T., & Selkoe, D. J. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505953112 · Cited by 184
“After our initial report (9), two laboratories published data supporting the earlier model of αS existing as natively unfolded monomers.”
BackgroundSelf-citationPost-translational modification of α-synuclein in Parkinson׳s disease
Barrett, P. J., & Greenamyre, J. T. (2015) · Brain Research · doi:10.1016/j.brainres.2015.06.002 · Cited by 175
α-synuclein aggregation and its modulation
Ghosh, D., Mehra, S., Sahay, S., Singh, P. K., & Maji, S. K. (2016) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2016.10.021 · Cited by 193
Structural, morphological, and functional diversity of amyloid oligomers
Breydo, L., & Uversky, V. N. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.07.013 · Cited by 177
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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