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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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Iron-responsive-like elements and neurodegenerative ferroptosisPreprint
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Self-citationThe neurotoxicity of pesticides: Implications for Parkinson's disease
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Biophysical groundwork as a hinge to unravel the biology of α-synuclein aggregation and toxicity
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“Under normal conditions, α-syn exists in two forms, mostly in the form of a monomer, but it also exists in the form of a helically folded tetramer, which maintains a dynamic balance with the monomer (Bartels et al., 2011).”
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“These hexameric repeats are believed to be responsible for the formation of an alpha-helical secondary structure (Bartels et al., 2011), which reacts with various intracellular membrane proteins.”
BackgroundDistinct higher-order α-synuclein oligomers induce intracellular aggregation
Illes‐Toth, E., Ramos, M. R., Cappai, R., Dalton, C., & Smith, D. P. (2015) · Biochemical Journal · doi:10.1042/bj20150159 · Cited by 37
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“A tetrameric form of αS has also been identified in human tissues that has been postulated as the inactive storage form of this structurally dynamic protein due to its aggregation resistance [6, 7].”
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Allen, S. G., Meade, R. M., Stenner, L. L. W., & Mason, J. M. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00675-8 · Cited by 39
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Effect of Osmolytes on Conformational Behavior of Intrinsically Disordered Protein α-Synuclein
Jahan, I., & Nayeem, S. M. (2019) · Biophysical Journal · doi:10.1016/j.bpj.2019.09.046 · Cited by 36
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Ebanks, K., Lewis, P. A., & Bandopadhyay, R. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01381 · Cited by 38
“Structural and biophysical analyses suggest that a membrane bound tetramer version of α-synuclein may represent the functional form of this protein (Bartels et al., 2011; Dettmer et al., 2013), although the physiological relevance of this remains a subject of debate (Fauvet et al., 2012; Theillet…”
BackgroundUpregulation of Cellular Palmitoylation Mitigates α‐Synuclein Accumulation and Neurotoxicity
Ho, G. P. H., Ramalingam, N., Imberdis, T., Wilkie, E. C., Dettmer, U., & Selkoe, D. J. (2020) · Movement Disorders · doi:10.1002/mds.28346 · Cited by 39
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“Under healthy conditions, α-Syn is a naturally unfolded and soluble monomer, although its presence as a tetramer has previously been discussed [4,5].”
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“vivo, but this vision was challenged by the groups of Selkoe and Petsko who argued that the true tetrameric nature of the protein vivo is destroyed during the purification steps to prod uce the recombinant protein [64, 65].”
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“Diverse physiological forms of α-syn have been reported: the protein may exist as unstructured monomer [9,10], α-helical monomer or multimer [11,12] that interacts with biological membranes [13].”
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Bellini, G., D’Antongiovanni, V., Palermo, G., Antonioli, L., Fornai, M., Ceravolo, R., Bernardini, N., Derkinderen, P., & Pellegrini, C. (2024) · Medicinal Research Reviews · doi:10.1002/med.22091 · Cited by 42
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“While the function of wild type α-synuclein still needs to be resolved, it is proposed to play a role in neurotransmitter release (Bartels et al. 2011), presynaptic vesicle formation (Chandra et al.”
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Cross‐linking for the analysis of α‐synuclein in the enteric nervous system
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“…ignited in 2011, when it was reported that, rather than being an unfolded monomer, alpha-synuclein exists primarily as a helical tetramer not only when heterologously expressed but also after purification from mammalian cells under non-denaturing conditions (Bartels et al. 2011; Wang et al. 2011).”
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“ability to interact with synaptic proteins, membranes, and vesicles (Bartels et al. 2011; Lashuel et al. 2013).”
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“In vitro studies using purified α-syn, however, revealed that acetylation can alter α-syn protein to aggregation resistant type by augmenting its α-helical structure (9, 28-31).”
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“a-syn may exist in a dynamic equilibrium between a disordered monomer and a tetramer under physiological conditions [58-61] would indicate that changes in both regions could abnormally alter monomer:tetramer a-syn”
BackgroundFate of Pup inside the Mycobacterium Proteasome Studied by in-Cell NMR
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“α-Syn is a 14 kDa unfolded and soluble cytoplasmic protein enriched in presynaptic nerve terminals that exists as either an intrinsically disordered monomer or an α-helical tetramer [3, 5, 10].”
BackgroundResidue Histidine 50 Plays a Key Role in Protecting α-Synuclein from Aggregation at Physiological pH
Chi, Y., Armstrong, G. S., Jones, D. N. M., Eisenmesser, E. Z., & Liu, C.-W. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.544049 · Cited by 33
“Syn(H50Q) Is a Native Unfolded Protein in Aqueous Buffers— Although Syn has long been considered as a native unfolded protein in aqueous buffers (35, 36), two recent studies have suggested that Syn existed as a homotetramer with an -helical conformation when it was purified using non-denaturing methods (37, 38).”
MethodNMDA and AMPA Receptors at Synapses: Novel Targets for Tau and α-Synuclein Proteinopathies
Italia, M., Ferrari, E. S., Luca, M. D., & Gardoni, F. (2022) · Biomedicines · doi:10.3390/biomedicines10071550 · Cited by 33
“This protein exists in the cell as a dynamic pool of monomers and multimers in an equilibrium between soluble and membrane bound states due to its high affinity to anionic membranes [58,59].”
BackgroundAnastasiadi, A. T., Arvaniti, V.-Z., Hudson, K. E., Kriebardis, A. G., Stathopoulos, C., D’Alessandro, A., Spitalnik, S. L., & Tzounakas, V. L. (2024) · Protein & Cell · doi:10.1093/procel/pwae001 · Cited by 35
“It occurs in a monomeric, intrinsically disordered form (Fauvet et al., 2012), which exists in equilibrium with a membrane-associated multimeric form (Bartels et al., 2011).”
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Unraveling the NaCl Concentration Effect on the First Stages of α-Synuclein Aggregation
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Research Priorities on the Role of α‐ Synuclein in Parkinson's Disease Pathogenesis
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Parkinson's disease as a member of Prion-like disorders
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“…such as protein turnover (Hwang et al., 2010; Shemorry et al., 2013;Myklebust et al., 2015; Xu et al., 2015; Sheikh et al., 2017), protein folding (Bartels et al., 2011; Trexler and Rhoades, 2012; Holmes et al., 2014), protein-protein interactions (Singer and Shaw, 2003; Coulton et al., 2010;…”
BackgroundA glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies
Hartlage‐Rübsamen, M., Bluhm, A., Moceri, S., Machner, L., Köppen, J., Schenk, M., Hilbrich, I., Holzer, M., Weidenfeller, M., Richter, F., et al. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02349-5 · Cited by 31
“Under physiological conditions, α-synuclein is believed to be a natively unfolded protein of 140 amino acids, but it may also exist as α-helically folded multimers [8, 25].”
Backgroundα-Synuclein-mediated neurodegeneration in Dementia with Lewy bodies: the pathobiology of a paradox
Simon, C. A., Soga, T., Okano, H. J., & Parhar, I. S. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00709-y · Cited by 35
Exploring the accessible conformations of N‐terminal acetylated α‐synuclein
Moriarty, G. M., Janowska, M. K., Kang, L., & Baum, J. (2013) · FEBS Letters · doi:10.1016/j.febslet.2013.02.049 · Cited by 32
“group by the recent report [25] of tetramer formation of asyn, asyn was studied from a variety of sources, some of which were mammalian and were likely to be N-terminally acetylated.”
InfluentialNarayanan, C., Weinstock, D. S., Wu, K., Baum, J., & Levy, R. M. (2012) · Journal of Chemical Theory and Computation · doi:10.1021/ct300241t · Cited by 34
McDowall, J., Ntai, I., Honeychurch, K. C., Hart, J. P., Colin, P., Schneider, B. L., & Brown, D. R. (2017) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2017.08.001 · Cited by 36
“It is a monomeric protein, but may form tetramers under specific conditions (Bartels et al., 2011; Dettmer et al., 2013).”
BackgroundWang, K., Zhang, C., Zhang, B., Li, G., Shi, G., Cai, Q., & Huang, M. (2022) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2022.114152 · Cited by 33
Copper trafficking systems in cells: insights into coordination chemistry and toxicity
Han, J. (2023) · Dalton Transactions · doi:10.1039/d3dt02166a · Cited by 33
Parkinson’s disease mutant Miro1 causes mitochondrial dysfunction and dopaminergic neuron loss
Chemla, A., Arena, G., Sacripanti, G., Barmpa, K., Žagare, A., Garcia, P., Gorgogietas, V. A., Antony, P. M. A., Ohnmacht, J., Baron, A., et al. (2025) · Brain · doi:10.1093/brain/awaf051 · Cited by 33
“Accumulation of the 60 kDa α -synuclein, possibly a tetramer form, 36,37 was also observed in PD-R272Q neurons compared to the iCtrl, but not the Ctrl (Fig.”
Neuronal microtubules and proteins linked to Parkinson’s disease: a relevant interaction?
Calogero, A. M., Mazzetti, S., Pezzoli, G., & Cappelletti, G. (2019) · Biological Chemistry · doi:10.1515/hsz-2019-0142 · Cited by 28
Immunotherapy Targeting Neurodegenerative Proteinopathies: α-Synucleinopathies and Tauopathies
Shin, J. H., Kim, H., & Jeon, B. (2019) · Journal of Movement Disorders · doi:10.14802/jmd.19057 · Cited by 31
The Role of Glial Mitochondria in α-Synuclein Toxicity
Jeon, Y., Kwon, Y., Jo, M., Lee, S., Kim, S., & Kim, H. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.548283 · Cited by 31
“Originally, α-syn was thought to be a natively unfolded monomeric protein, but recent studies have indicated that α-syn forms an α-helix-rich tetramer (Bartels et al., 2011; Wang et al., 2011, 2014; Dettmer et al., 2013, 2015; Gurry et al., 2013; Burre et al., 2014).”
BackgroundDent, S. E., King, D. P., Osterberg, V. R., Adams, E. K., Mackiewicz, M. R., Weissman, T. A., & Unni, V. K. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101552 · Cited by 34
“The physiologically and pathologically relevant conformations of aSyn are subject to debate, and questions remain about the role/s of the unfolded monomeric state (59, 60), as well as a tetrameric structure that it can also form (61).”
BackgroundA Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity
Nuber, S., Chung, C. Y., Tardiff, D. F., Bechade, P. A., McCaffery, T. D., Shimanaka, K., Choi, J., Chang, B., Raja, W. K., Neves, E., et al. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01199-7 · Cited by 33
Self-citationFonseca‐Ornelas, L., Stricker, J. M. S., Soriano-Cruz, S., Weykopf, B., Dettmer, U., Muratore, C., Scherzer, C. R., & Selkoe, D. J. (2022) · npj Parkinson s Disease · doi:10.1038/s41531-022-00380-1 · Cited by 31
Self-citationBlood based biomarkers for movement disorders
Morris, H. R. (2022) · Acta Neurologica Scandinavica · doi:10.1111/ane.13700 · Cited by 29
N‐homocysteinylation of α‐synuclein promotes its aggregation and neurotoxicity
Zhou, L., Guo, T., Meng, L., Zhang, X., Tian, Y., Dai, L., Niu, X., Li, Y., Liu, C., Chen, G., et al. (2022) · Aging Cell · doi:10.1111/acel.13745 · Cited by 30
“Under physiological conditions, α- syn is a natively unstructured synaptic protein that is mainly expressed in the presynaptic nerve terminals (Bartels et al., 2011).”
BackgroundIs Parkinson’s Disease Truly a Prion-Like Disorder? An Appraisal of Current Evidence
Chauhan, A., & Jeans, A. F. (2015) · Neurology Research International · doi:10.1155/2015/345285 · Cited by 34
Trexler, A., & Rhoades, E. R. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8338-x · Cited by 31
“AS is generally thought to be an intrinsically disordered monomer in solution, although there is recent evidence that it may be capable of forming a partially α-helical tetramer under some conditions [5, 6].”
Aelvoet, S., Ibrahimi, A., Macchi, F., Gijsbers, R., den Haute, C. V., Debyser, Z., & Baekelandt, V. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.4933-13.2014 · Cited by 31
“This approach previously allowed detection of different sizes of endogenous SYN oligomers in human erythro- leukemia cells (Bartels et al., 2011; Dettmer et al., 2013).”
BackgroundStimulation of synaptoneurosome glutamate release by monomeric and fibrillated α‐synuclein
Sarafian, T. A., Littlejohn, K., Yuan, S. Y., Fernandez, C., Cilluffo, M. C., Koo, B., Whitelegge, J. P., & Watson, J. B. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24024 · Cited by 29
“Membrane interaction by a subpopulation of a-helical tetrameric forms of asynuclein also cannot be ruled out (Bartels et al., 2011; Wang et al., 2011).”
BackgroundDashtipour, K., Tafreshi, A., Adler, C. H., Beach, T. G., Chen, X., Serrano, G. E., Tashiro, S., & Wang, C. (2017) · Brain Sciences · doi:10.3390/brainsci7070074 · Cited by 30
“Considered an unstructured soluble protein, un-mutated α-synuclein may occur physiologically as a monomer or a helically folded tetramer that resists aggregation [15].”
Backgroundα-Synuclein Aggregation and Modulating Factors
Paleologou, K. E., & El‐Agnaf, O. M. A. (2012) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-007-5416-4_6 · Cited by 33
“(Bartels et al. 2011).”
Siwecka, N., Saramowicz, K., Galita, G., Rozpędek‐Kamińska, W., & Majsterek, I. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15082051 · Cited by 33
“It has been suggested that physiological α-syn may mainly present as α-helical tetramers, but this theory is controversial and has not yet been fully confirmed [106].”
BackgroundPeripheral proteinopathy in neurodegenerative diseases
Xu, B., Lei, X., Yang, Y., Yu, J., Chen, J., Xu, Z., Ye, K., & Zhang, J. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-024-00461-6 · Cited by 31
Jonsson, O., Steffen, A.-C., Sundquist, V. S., Janson, J., Martinsson, S., Määttä, U., & Breitholtz‐Emanuelsson, A. (2013) · Bioanalysis · doi:10.4155/bio.12.337 · Cited by 29
Breaking the Code of Amyloid- β Oligomers
Lesné, S. (2013) · International Journal of Cell Biology · doi:10.1155/2013/950783 · Cited by 29
The role of the protein–RNA recognition code in neurodegeneration
Nahálka, J. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03096-3 · Cited by 29
Modeling Cell-Cell Interactions in Parkinson’s Disease Using Human Stem Cell-Based Models
Simmnacher, K., Lanfer, J., Rizo, T., Kaindl, J., & Winner, B. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00571 · Cited by 32
“Studies detected a physiological tetrameric α-Syn species, resistant to aggregation (Bartels et al., 2011; Wang et al., 2011; Dettmer et al., 2015b).”
BackgroundRoles for α-Synuclein in Gene Expression
Somayaji, M., Lanseur, Z., Choi, S. J., Sulzer, D., & Mosharov, E. V. (2021) · Genes · doi:10.3390/genes12081166 · Cited by 32
“In its monomeric state, the protein is soluble and intrinsically unfolded, but has also been identified as a helically folded tetramer under physiological conditions [1].”
BackgroundN-alpha-acetylation of Huntingtin protein increases its propensity to aggregate
Gottlieb, L., Guo, L. E., Shorter, J., & Marmorstein, R. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101363 · Cited by 29
“engineered into MCSI of a pET DUET vector containing a TEV proteasecleavable 6XHis-tag with MCSII containing Naa10p (1-156) to co-express the heterodimeric SpNatA complex with”
BackgroundMethodThe amyloid state of proteins: A boon or bane?
Hassan, M. N., Nabi, F., Khan, A. N., Hussain, M. S., Siddiqui, W. A., Uversky, V. N., & Khan, R. H. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.01.115 · Cited by 30
Lackie, R. E., de Miranda, A. S., Lim, M. P., Novikov, V., Madrer, N., Karunatilleke, N. C., Rutledge, B. S., Tullo, S., Brickenden, A. M., Maitland, M. E. R., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02491-8 · Cited by 29
Potential role of α‐synuclein in neurodegeneration: studies in a rat animal model
Stoica, G., Lungu, G. F., Bjorklund, N. L., Taglialatela, G., Zhang, X., Chiu, V. M., Hill, H. H., Schenk, J. O., & Murray, I. V. J. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07805.x · Cited by 29
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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