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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In human brain lysates, human neuronal cultures, mouse models, and cell lines expressing familial PD αSyn mutations (A53T or E46K), a decrease in the tetramer:monomer ratio correlates with increased neurotoxicity.
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Spillantini, M. G., Schmidt, M. L., Lee, V. M.-Y., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997) · Nature · doi:10.1038/42166 · Cited by 8,382 · see citing works
Microdetermination of Phosphorus
Chen, P. S., Toribara, T. Y., & Warner, H. R. (1956) · Analytical Chemistry · doi:10.1021/ac60119a033 · Cited by 7,240 · see citing works
Chen, Y., Yang, J. T., & Martínez, H. M. (1972) · Biochemistry · doi:10.1021/bi00772a015 · Cited by 1,953 · see citing works
Stabilization of α-Synuclein Secondary Structure upon Binding to Synthetic Membranes
Davidson, W. S., Jonas, A., Clayton, D. F., & George, J. M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.16.9443 · Cited by 1,588 · see citing works
NACP, A Protein Implicated in Alzheimer's Disease and Learning, Is Natively Unfolded
Weinreb, P. H., Zhen, W., Poon, A. W., Conway, K. A., & Lansbury, P. T. (1996) · Biochemistry · doi:10.1021/bi961799n · Cited by 1,524 · see citing works
Missing pieces in the Parkinson's disease puzzle
Obeso, J. A., Rodríguez‐Oroz, M., Goetz, C. G., Marin, C. A., Kordower, J. H., Rodrı́guez, M., Hirsch, É. C., Farrer, M. J., Schapira, A. H. V., & Halliday, G. M. (2010) · Nature Medicine · doi:10.1038/nm.2165 · Cited by 737 · see citing works
A century-old debate on protein aggregation and neurodegeneration enters the clinic
Lansbury, P. T., & Lashuel, H. A. (2006) · Nature · doi:10.1038/nature05290 · Cited by 681 · see citing works
The two faces of protein misfolding: gain‐ and loss‐of‐function in neurodegenerative diseases
Winklhofer, K. F., Tatzelt, J., & Haass, C. (2008) · The EMBO Journal · doi:10.1038/sj.emboj.7601930 · Cited by 395 · see citing works
Sharon, R., Goldberg, M. S., Bar-Josef, I., Betensky, R. A., Shen, J., & Selkoe, D. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.171300598 · Cited by 329 · see citing works
Self-citationGATA transcription factors directly regulate the Parkinson's disease-linked gene α-synuclein
Scherzer, C. R., Grass, J. A., Liao, Z., Pepivani, I., Zheng, B., Eklund, A. C., Ney, P. A., Ng, J., McGoldrick, M., Mollenhauer, B., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802437105 · Cited by 271 · see citing works
Advantages and limitations of clear‐native PAGE
Wittig, I., & Schägger, H. (2005) · PROTEOMICS · doi:10.1002/pmic.200500081 · Cited by 264 · see citing works
Membrane Association and Protein Conformation of α-Synuclein in Intact Neurons
McLean, P. J., Kawamata, H., Ribich, S. A., & Hyman, B. T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8812 · Cited by 243 · see citing works
Tong, J., Wong, H., Guttman, M., Ang, L. C., Forno, L. S., Shimadzu, M., Rajput, A. H., Muenter, M. D., Kish, S. J., Hornykiewicz, O., et al. (2009) · Brain · doi:10.1093/brain/awp282 · Cited by 204 · see citing works
The Tetrameric Protein Transthyretin Dissociates to a Non-native Monomer in Solution
Quintas, A., Saraiva, M. J., & Brito, R. M. M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.46.32943 · Cited by 187 · see citing works
Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses
Connelly, S., Choi, S., Johnson, S. M., Kelly, J. W., & Wilson, I. A. (2010) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2009.12.009 · Cited by 176 · see citing works
What causes cell death in Parkinson's disease?
Gupta, A., Dawson, V. L., & Dawson, T. M. (2009) · Annals of Neurology · doi:10.1002/ana.21573 · Cited by 144 · see citing works
Cryoelectron Microscopy Structure of Purified γ-Secretase at 12 Å Resolution
Osenkowski, P., Li, H. L., Ye, W., Li, D., Aeschbach, L., Fraering, P. C., Wolfe, M. S., Selkoe, D. J., & Li, H. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.10.078 · Cited by 116 · see citing works
Self-citationMechanistic aspects of Parkinson’s disease: α-synuclein and the biomembrane
Beyer, K. (2007) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-007-0014-9 · Cited by 104 · see citing works
Tsika, E., Moysidou, M., Guo, J., Cushman-Nick, M., Gannon, P. J., Sandaltzopoulos, R., Giasson, B. I., Krainc, D., Ischiropoulos, H., & Mazzulli, J. R. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4977-09.2010 · Cited by 99 · see citing works
Detection of novel intracellular O‐synuclein oligomeric species by fluorescence lifetime imaging
Klucken, J., Outeiro, T. F., Nguyen, P. T., McLean, P. J., & Hyman, B. T. (2006) · The FASEB Journal · doi:10.1096/fj.05-5422com · Cited by 83 · see citing works
Missense tau mutations identified in FTDP-17 have a small effect on tau–microtubule interactions
Deture, M. A., Ko, L., Yen, S. H., Nacharaju, P., Easson, C., Lewis, J. M., van Slegtenhorst, M., Hutton, M. L., & Yen, S.-H. C. (2000) · Brain Research · doi:10.1016/s0006-8993(99)02124-1 · Cited by 81 · see citing works
Smith, D. P., Tew, D. J., Hill, A. F., Bottomley, S., Masters, C. L., Barnham, K. J., & Cappai, R. (2008) · Biochemistry · doi:10.1021/bi701522m · Cited by 66 · see citing works
Ko, L., Ko, H.-H. C., Lin, W.-L., Kulathingal, J. G., & Yen, S.-H. C. (2008) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31818c3618 · Cited by 44 · see citing works
Mass Mapping of Large Globin Complexes by Scanning Transmission Electron Microscopy
Wall, J. S., Simon, M. N., Lin, B. Y., & Vinogradov, S. N. (2008) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(08)36027-3 · Cited by 19 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [20]Wang W The Parkinson disease-associated protein alpha-synuclein is folded in solution Proceedings of the National Academy of Sciences of the United States of America
Cited by
Sorted by citations
The many faces of α-synuclein: from structure and toxicity to therapeutic target
Lashuel, H. A., Overk, C., Oueslati, A., & Masliah, E. (2012) · Nature reviews. Neuroscience · doi:10.1038/nrn3406 · Cited by 1,623 · see citing works
“Although Bartels et al.(126) reported that chemical crosslinking of native α‐syn primarily stabilized α‐syn tetramers, studies by several groups, including the work by Wang et al.”
Resultα-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies
Wong, Y. C., & Krainc, D. (2017) · Nature Medicine · doi:10.1038/nm.4269 · Cited by 897 · see citing works
Bendor, J. T., Logan, T. P., & Edwards, R. H. (2013) · Neuron · doi:10.1016/j.neuron.2013.09.004 · Cited by 825 · see citing works
α‐Synuclein aggregation nucleates through liquid‐liquid phase separation
Ray, S., Singh, N., Kumar, R., Patel, K., Pandey, S., Datta, D., Mahato, J., Panigrahi, R., Navalkar, A., Mehra, S., et al. (2020) · Nature Chemistry · doi:10.1038/s41557-020-0465-9 · Cited by 863 · see citing works
Structural disorder of monomeric α-synuclein persists in mammalian cells
Theillet, F., Binolfi, A., Bekei, B., Martorana, A., Rose, H. M., Stuiver, M., Verzini, S., Lorenz, D., van Rossum, M., Goldfarb, D., et al. (2016) · Nature · doi:10.1038/nature16531 · Cited by 877 · see citing works
Calabresi, P., Mechelli, A., Natale, G., Volpicelli‐Daley, L. A., Lazzaro, G. D., & Ghiglieri, V. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05672-9 · Cited by 836 · see citing works
“A-syn has long been defined as a ‘natively unfolded’ monomer; however, it has been demonstrated that endogenous α-syn naturally occurs in large part as a folded tetramer of about 58 KDa with little or no amyloid-like aggregation potential [7].”
BackgroundAlpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease
Rocha, E. M., Miranda, B. D., & Sanders, L. H. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.04.004 · Cited by 769 · see citing works
Nguyen, P. H., Ramamoorthy, A., Sahoo, B. R., Zheng, J., Faller, P., Straub, J. E., Domı́nguez, L., Shea, J., Dokholyan, N. V., Simone, A. D., et al. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c01122 · Cited by 676 · see citing works
Buell, A. K., Galvagnion, C., Gaspar, R., Sparr, E., Vendruscolo, M., Knowles, T. P. J., Linse, S. S., & Dobson, C. M. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1315346111 · Cited by 666 · see citing works
Exner, N., Lutz, A. K., Haass, C., & Winklhofer, K. F. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.170 · Cited by 652 · see citing works
“…under non-denaturing conditions adopts a helically folded tetrameric structure with enhanced lipid-binding capacity and markedly reduced aggregation propensity in comparison with a -synuclein monomers, suggesting that a -synuclein tetramers are the physiological species (Bartels et al , 2011).”
Spotlight on protein N-terminal acetylation
Ree, R., Varland, S., & Arnesen, T. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0116-z · Cited by 648 · see citing works
Cell Biology and Pathophysiology of α-SynucleinPreprint
Burré, J., Sharma, M., & Südhof, T. C. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024091 · Cited by 576 · see citing works
The Synaptic Function of α-Synuclein
Burré, J. (2015) · Journal of Parkinson s Disease · doi:10.3233/jpd-150642 · Cited by 579 · see citing works
Fauvet, B., Mbefo, M. K., Fares, M.-B., Desobry, C., Michael, S. A., Ardah, M. T., Tsika, E., Coune, P., Prudent, M., Lion, N., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.318949 · Cited by 565 · see citing works
“(1) because they did not detect any SDS-stable oligomers in their samples of -syn purified from RBCs.”
BackgroundMethodInfluentialParkinson’s Disease: Etiology, Neuropathology, and Pathogenesis
Kouli, A., Torsney, K., & Kuan, W. (2018) · Codon Publications eBooks · doi:10.15586/codonpublications.parkinsonsdisease.2018.ch1 · Cited by 556 · see citing works
“Native α-synuclein in the brain is mostly unfolded without a defined tertiary structure (109), although in aqueous solutions it can be present in stable tetramers that resist aggregation (110).”
Dehay, B., Bourdenx, M., Gorry, P., Przedborski, S., Vila, M., Hunot, S., Singleton, A., Olanow, C. W., Merchant, K., Bézard, E., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)00006-x · Cited by 530 · see citing works
Phase separation and neurodegenerative diseases: a disturbance in the force
Zbinden, A., Pérez-Berlanga, M., De Rossi, P., & Polymenidou, M. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.09.014 · Cited by 500 · see citing works
Physicochemical Properties of Cells and Their Effects on Intrinsically Disordered Proteins (IDPs)
Theillet, F., Binolfi, A., Frembgen-Kesner, T., Hingorani, K. S., Sarkar, M., Kyne, C., Li, C., Crowley, P. B., Gierasch, L. M., Pielak, G. J., et al. (2014) · Chemical Reviews · doi:10.1021/cr400695p · Cited by 504 · see citing works
Oxidative stress and cellular pathologies in Parkinson’s disease
Puspita, L., Chung, S. Y., & Shim, J. (2017) · Molecular Brain · doi:10.1186/s13041-017-0340-9 · Cited by 486 · see citing works
“A growing body of work suggests that the monomer and tetramer types are the physiological forms of α-synuclein, while oligomers and fibrils are the pathogenic forms [75, 76].”
BackgroundDirect observation of the three regions in α-synuclein that determine its membrane-bound behaviour
Fusco, G., Simone, A. D., Gopinath, T., Vostrikov, V. V., Vendruscolo, M., Dobson, C. M., & Veglia, G. (2014) · Nature Communications · doi:10.1038/ncomms4827 · Cited by 483 · see citing works
“In aqueous solutions 9 as well as in cellular milieu 10 , α S has been shown to behave as an intrinsically disordered protein, although there has been evidence for and against the possible existence of more highly structured forms of soluble α S in some environments and in complexes 41, 42 .”
A soluble α-synuclein construct forms a dynamic tetramer
Wang, W., Perovic, I., Chittuluru, J., Kaganovich, A., Nguyen, L. T. T., Liao, J., Auclair, J. R., Johnson, D., Landeru, A., Simorellis, A. K., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113260108 · Cited by 478 · see citing works
“Further, WT αSyn isolated under nondenaturing conditions from neuronal and red blood cells behaves as a stable tetramer with properties, including helical content as estimated by CD, virtually identical to those of the recombinant protein reported here (9).”
BackgroundBurré, J., Sharma, M., & Südhof, T. C. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1416598111 · Cited by 478 · see citing works
“This view was challenged when α-synuclein purified from human erythrocytes was found to be a stably folded tetramer, as judged by analytical ultracentrifugation (33).”
BackgroundRegulation of proteasome activity in health and disease
Schmidt, M., & Finley, D. J. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.08.012 · Cited by 461 · see citing works
“As tau, α-synuclein monomers are unfolded [171] and can be degraded by”
Defects in trafficking bridge Parkinson’s disease pathology and genetics
Abeliovich, A., & Gitler, A. D. (2016) · Nature · doi:10.1038/nature20414 · Cited by 462 · see citing works
Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles
Meade, R. M., Fairlie, D. P., & Mason, J. M. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0329-1 · Cited by 430 · see citing works
Targeting protein aggregation for the treatment of degenerative diseases
Eisele, Y. S., Monteiro, C., Fearns, C., Encalada, S. E., Wiseman, R. L., Powers, E. T., & Kelly, J. W. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4593 · Cited by 416 · see citing works
α-synuclein in the pathophysiology of Alzheimer’s disease
Twohig, D., & Nielsen, H. M. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0320-x · Cited by 374 · see citing works
Review: Sporadic Parkinson's disease: development and distribution ofα‐synuclein pathology
Tredici, K. D., & Braak, H. (2015) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12298 · Cited by 396 · see citing works
Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion‐Like Disorder?
Olanow, C. W., & Brundin, P. (2013) · Movement Disorders · doi:10.1002/mds.25373 · Cited by 392 · see citing works
“These could include therapies that maintain a-synuclein in a stable tetrameric form that resists misfolding, which, despite some controversy,(68) has been suggested to be its native form.(44) Another approach could be to knock out native a-syn-”
BackgroundSchapira, A. H. V., Olanow, C. W., Greenamyre, J. T., & Bézard, E. (2014) · The Lancet · doi:10.1016/s0140-6736(14)61010-2 · Cited by 392 · see citing works
Acceleration of α-Synuclein Aggregation by Exosomes
Grey, M., Dunning, C. J. R., Gaspar, R., Grey, C. E., Brundin, P., Sparr, E., & Linse, S. S. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.585703 · Cited by 378 · see citing works
“-syn has been suggested to exist in a tetrameric state in vivo, although the relevance and existence of this form is debated (46, 47).”
BackgroundAlpha-Synuclein Oligomers—Neurotoxic Molecules in Parkinson's Disease and Other Lewy Body Disorders
Ingelsson, M. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00408 · Cited by 374 · see citing works
“One research group has proposed that the normal cellular state of the protein is a tetrameric complex, which needs to dissociate before the monomers can start to aggregate (Bartels et al., 2011; Dettmer et al., 2013).”
BackgroundAlpha-synuclein biology in Lewy body diseases
Kim, W. S., Kågedal, K., & Halliday, G. M. (2014) · Alzheimer s Research & Therapy · doi:10.1186/s13195-014-0073-2 · Cited by 376 · see citing works
Oueslati, A. (2016) · Journal of Parkinson s Disease · doi:10.3233/jpd-160779 · Cited by 375 · see citing works
Neuropathology and molecular diagnosis of Synucleinopathies
Koga, S., Sekiya, H., Kondru, N. C., Ross, O. A., & Dickson, D. W. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00501-z · Cited by 338 · see citing works
Properties of native brain α-synuclein
Burré, J., Vivona, S., Diao, J., Sharma, M., Brünger, A. T., & Südhof, T. C. (2013) · Nature · doi:10.1038/nature12125 · Cited by 340 · see citing works
Alpha-synuclein oligomers: a new hope
Bengoa‐Vergniory, N., Roberts, R. F., Wade‐Martins, R., & Alegre‐Abarrategui, J. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1755-1 · Cited by 335 · see citing works
“1 3 that native a-syn exists physiologically as a folded helical tetramer that is resistant to fibrillization and thus distinct from pathological oligomers [8, 34, 96, 156].”
BackgroundImplications of peptide assemblies in amyloid diseases
Ke, P. C., Sani, M., Ding, F., Käkinen, A., Javed, I., Separovic, F., Davis, T. P., & Mezzenga, R. (2017) · Chemical Society Reviews · doi:10.1039/c7cs00372b · Cited by 338 · see citing works
Targeting Alpha-Synuclein as a Therapy for Parkinson’s Disease
Fields, C. R., Bengoa‐Vergniory, N., & Wade‐Martins, R. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00299 · Cited by 336 · see citing works
“Although the majority of studies suggest that cytosolic α-syn is present within cells as an intrinsically unfolded monomer, alternative hypotheses have proposed that it exists as a tetrameric alpha-helical oligomer that is resistant to fibrillization and thus distinct from pathological variants (Bartels et al., 2011;…”
BackgroundDettmer, U., Newman, A. J., Soldner, F., Luth, E. S., Kim, N. C., von Saucken, V. E., Sanderson, J. B., Jaenisch, R., Bartels, T., & Selkoe, D. (2015) · Nature Communications · doi:10.1038/ncomms8314 · Cited by 317 · see citing works
Self-citationThe physiological role of α‐synuclein and its relationship to Parkinson’s Disease
Sulzer, D., & Edwards, R. H. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14810 · Cited by 310 · see citing works
Glucocerebrosidase and its relevance to Parkinson disease
Do, J., McKinney, C. E., Sharma, P., & Sidransky, E. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0336-2 · Cited by 304 · see citing works
Alpha-synuclein and Protein Degradation Systems: a Reciprocal Relationship
Xilouri, M., Brekk, O. R., & Stefanis, L. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8341-2 · Cited by 299 · see citing works
“In view of the recent findings supporting the notion that alpha-synuclein exists physiologically as a tetramer with decreased aggregation propensity [87], while the PDlinked mutants (A30P, E46K, and A53T) markedly decrease the stability of the tetramer and shift alpha-synuclein equilibrium towards the “toxic” monomer…”
A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration
Walsh, D. M., & Selkoe, D. J. (2016) · Nature reviews. Neuroscience · doi:10.1038/nrn.2016.13 · Cited by 290 · see citing works
Self-citationα‐Synuclein oligomers and clinical implications for Parkinson disease
Kalia, L. V., Kalia, S. K., McLean, P. J., Lozano, A. M., & Lang, A. E. (2012) · Annals of Neurology · doi:10.1002/ana.23746 · Cited by 295 · see citing works
Alpha-synuclein: from secretion to dysfunction and death
Marques, O., & Outeiro, T. F. (2012) · Cell Death and Disease · doi:10.1038/cddis.2012.94 · Cited by 287 · see citing works
“Recently, aSyn was suggested to exist, physiologically, as a folded tetramer.(83) Moreover, it was shown that the tetrameric form of aSyn resists aggregation.”
BackgroundFanning, S., Haque, A., Imberdis, T., Baru, V., Barrasa, M. I., Nuber, S., Termine, D., Ramalingam, N., Ho, G. P. H., Noble, T., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2018.11.028 · Cited by 285 · see citing works
Self-citationLuth, E. S., Stavrovskaya, I. G., Bartels, T., Kristal, B. S., & Selkoe, D. J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.545749 · Cited by 281 · see citing works
“In the context of PD, our data support the pursuit of therapeutic strategies designed to stabilize native, aggregation-resistant -helical tetramers and related oligomers in neurons (7, 9).”
BackgroundSelf-citationAmyloid β-protein oligomers and Alzheimer’s disease
Hayden, E. Y., & Teplow, D. B. (2013) · Alzheimer's Research & Therapy · doi:10.1186/alzrt226 · Cited by 276 · see citing works
“tetramer [117].”
Integrating Pathways of Parkinson's Disease in a Molecular Interaction Map
Fujita, K., Ostaszewski, M., Matsuoka, Y., Ghosh, S., Glaab, E., Trefois, C., Crespo, I., Perumal, T. M., Jurkowski, W., Antony, P. M. A., et al. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8489-4 · Cited by 270 · see citing works
“oligomerisation and fibrilisation [120–122].”
α-Synuclein Multimers Cluster Synaptic Vesicles and Attenuate Recycling
Wang, L., Das, U., Scott, D. A., Tang, Y., McLean, P. J., & Roy, S. (2014) · Current Biology · doi:10.1016/j.cub.2014.08.027 · Cited by 275 · see citing works
Roberts, R. F., Wade‐Martins, R., & Alegre‐Abarrategui, J. (2015) · Brain · doi:10.1093/brain/awv040 · Cited by 272 · see citing works
“Although it is possible that AS-PLA is detecting a range of alpha-synuclein oligomeric species, it is unlikely that AS-PLA detects the recently proposed physiological tetrameric form of alpha-synuclein (Bartels et al., 2011; Wang et al., 2011) for a number of reasons.”
BackgroundInhibition of Amyloid Formation
Härd, T., & Lendel, C. (2012) · Journal of Molecular Biology · doi:10.1016/j.jmb.2011.12.062 · Cited by 266 · see citing works
Van der Perren, A., Gelders, G., Fenyi, A., Bousset, L., Brito, F., Peelaerts, W., Van den Haute, C., Gentleman, S., Melki, R., & Baekelandt, V. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02157-3 · Cited by 277 · see citing works
α-Synuclein promotes dilation of the exocytotic fusion pore
Logan, T., Bendor, J., Toupin, C., Thorn, K., & Edwards, R. H. (2017) · Nature Neuroscience · doi:10.1038/nn.4529 · Cited by 267 · see citing works
“Due perhaps to conformational specificity for the membrane-bound or multimeric protein 43–45 , this antibody thus provides what may be the first direct histological evidence for the specific localization of synuclein to neurosecretory vesicles, indicating the potential for a direct effect on…”
Role of α-Synuclein in Inducing Innate and Adaptive Immunity in Parkinson Disease
Allen Reish, H. E., & Standaert, D. G. (2015) · Journal of Parkinson’s Disease · doi:10.3233/jpd-140491 · Cited by 244 · see citing works
Benskey, M. J., Perez, R. G., & Manfredsson, F. P. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13570 · Cited by 247 · see citing works
Therapeutic approaches to target alpha-synuclein pathology
Brundin, P., Dave, K. D., & Kordower, J. H. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.10.003 · Cited by 244 · see citing works
“, 2017), and possibly also as a tetramer (Bartels et al., 2011), although the existence of a tetrameric form is debated (Fauvet et al.”
Protein misfolding and aggregation in Alzheimer’s disease and type 2 diabetes mellitus
Ashraf, G., Greig, N., Khan, T., Hassan, I., Tabrez, S., Shakil, S., Sheikh, I., Zaidi, S., Akram, M., Jabir, N., et al. (2014) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527313666140917095514 · Cited by 236 · see citing works
Pathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease
Overk, C. R., & Masliah, E. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.015 · Cited by 242 · see citing works
The Role of α-Synuclein Oligomers in Parkinson’s Disease
Du, X.-Y., Xie, X.-X., & Liu, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228645 · Cited by 242 · see citing works
Pratt, W. B., Gestwicki, J. E., Osawa, Y., & Lieberman, A. P. (2014) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010814-124332 · Cited by 237 · see citing works
“However, a recent careful study of endogenous α-synuclein reveals that α-synuclein occurs physiologically as an α-helically folded, ∼58 kDa homotetramer (94).”
Parkinson’s disease: proteinopathy or lipidopathy?
Fanning, S., Selkoe, D. J., & Dettmer, U. (2020) · npj Parkinson s Disease · doi:10.1038/s41531-019-0103-7 · Cited by 238 · see citing works
Self-citationXu, L., & Pu, J. (2016) · Parkinson s Disease · doi:10.1155/2016/1720621 · Cited by 237 · see citing works
Cysteine cathepsins are essential in lysosomal degradation of α-synuclein
McGlinchey, R. P., & Lee, J. C. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1500937112 · Cited by 231 · see citing works
Copper Ions and Parkinson’s Disease: Why Is Homeostasis So Relevant?
Bisaglia, M., & Bubacco, L. (2020) · Biomolecules · doi:10.3390/biom10020195 · Cited by 226 · see citing works
Structure, function and toxicity of alpha‐synuclein: the Bermuda triangle in synucleinopathies
Villar‐Piqué, A., da Fonseca, T. L., & Outeiro, T. F. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13249 · Cited by 226 · see citing works
“Native a-syn tetramers enriched in alpha-helical structure were also reported after non-denaturing purification from mammalian cells (Bartels et al. 2011).”
BackgroundReversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide
Zunke, F., Moise, A. C., Belur, N. R., Gelyana, E., Stojkovska, I., Dzaferbegovic, H., Toker, N., Jeon, S., Fredriksen, K., & Mazzulli, J. R. (2017) · Neuron · doi:10.1016/j.neuron.2017.12.012 · Cited by 222 · see citing works
“For example, monomers and higher-order conformers of a-syn have been documented under physiological conditions, some with defined quaternary structure (Bartels et al., 2011; Burré et al., 2014; Cole et al., 2002; Gould et al., 2014; Wang et al., 2011, 2014).”
DisProt: intrinsic protein disorder annotation in 2020
Hatos, A., Hajdu-Soltész, B., Monzón, A. M., Palópoli, N., Álvarez, L., Fas, B. A., Bassot, C., Benítez, G. I., Bevilacqua, M., Chasapi, A., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz975 · Cited by 224 · see citing works
“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).”
MethodDettmer, U., Newman, A. J., Luth, E. S., Bartels, T., & Selkoe, D. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.403311 · Cited by 221 · see citing works
“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
Maltsev, A. S., Ying, J., & Bax, A. (2012) · Biochemistry · doi:10.1021/bi300642h · Cited by 217 · see citing works
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 216 · see citing works
“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 213 · see citing works
“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 213 · see citing works
Seeking a Mechanism for the Toxicity of Oligomeric α-Synuclein
Hall‐Roberts, H., & Brown, D. R. (2015) · Biomolecules · doi:10.3390/biom5020282 · Cited by 213 · see citing works
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 211 · see citing works
“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 · see citing works
Chung, S. Y., Kishinevsky, S., Mazzulli, J. R., Graziotto, J. J., Mrejeru, A., Mosharov, E. V., Puspita, L., Valiulahi, P., Sulzer, D. L., Milner, T. A., et al. (2016) · Stem Cell Reports · doi:10.1016/j.stemcr.2016.08.012 · Cited by 201 · see citing works
“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 210 · see citing works
“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 · see citing works
“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 204 · see citing works
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 · see citing works
“…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 199 · see citing works
Monomeric Synucleins Generate Membrane Curvature
Westphal, C. H., & Chandra, S. S. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.418871 · Cited by 199 · see citing works
“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 195 · see citing works
“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 202 · see citing works
“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 189 · see citing works
“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 188 · see citing works
“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 186 · see citing works
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 · see citing works
“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 185 · see citing works
“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 185 · see citing works
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 183 · see citing works
Sorrentino, Z. A., Giasson, B. I., & Chakrabarty, P. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-01977-2 · Cited by 181 · see citing works
“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 179 · see citing works
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 179 · see citing works
“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 177 · see citing works
“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 · see citing works
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 175 · see citing works
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 173 · see citing works
- 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 › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
