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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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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
Microdetermination of Phosphorus
Chen, P. S., Toribara, T. Y., & Warner, H. R. (1956) · Analytical Chemistry · doi:10.1021/ac60119a033 · Cited by 7,200
Chen, Y., Yang, J. T., & Martínez, H. M. (1972) · Biochemistry · doi:10.1021/bi00772a015 · Cited by 1,958
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 1,622
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
Missing pieces in the Parkinson's disease puzzle
Obeso, J. A., Rodríguez-Oroz, M. C., 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 776
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 691
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 410
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 340
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
Cited by
Sorted by citations
Items 801–900 of 999
Sakai, R., Suzuki, M., Ueyama, M., Takeuchi, T., Minakawa, E. N., Hayakawa, H., Baba, K., Mochizuki, H., & Nagai, Y. (2019) · PLoS ONE · doi:10.1371/journal.pone.0218261 · Cited by 14
Small molecule-based fluorescent probes for the detection of α-Synuclein aggregation states
Haque, R., & Maity, D. (2023) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2023.129257 · Cited by 15
The Effects of Lipids on α-Synuclein Aggregation In Vitro
Ramirez, J., Pancoe, S. X., Rhoades, E. R., & Petersson, E. J. (2023) · Biomolecules · doi:10.3390/biom13101476 · Cited by 15
Limanaqi, F., Zecchini, S., Saulle, I., Strizzi, S., Vanetti, C., Garziano, M., Cappelletti, G., Parolin, D., Caccia, S., Trabattoni, D., et al. (2024) · Biological Research · doi:10.1186/s40659-023-00482-x · Cited by 14
Development of in vitro model of exosome transport in microfluidic gut-brain axis-on-a-chip
Seo, G. M., Lee, H., Kang, Y. J., Kim, D., & Sung, J. H. (2024) · Lab on a Chip · doi:10.1039/d4lc00490f · Cited by 14
Ramalingam, M., & Kim, S.-J. (2016) · Journal of Receptors and Signal Transduction · doi:10.3109/10799893.2016.1171342 · Cited by 14
A sticky situation: Aberrant protein–protein interactions in Parkinson’s disease
Brown, J., & Horrocks, M. H. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.05.006 · Cited by 14
de Vondel, E. V., Baatsen, P., Elzen, R. V., Lambeir, A., Keiderling, T. A., Herrebout, W., & Johannessen, C. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b00780 · Cited by 14
α -Synuclein Trafficking in Parkinson’s Disease: Insights From Fly and Mouse Models
Cheng, J., Lu, Q., Li, S., & Ho, M. S.-C. (2018) · ASN NEURO · doi:10.1177/1759091418812587 · Cited by 14
“Physiologically, a-Syn forms helically folded tetramers that resist aggregation (Bartels et al., 2011; Wang et al., 2011).”
BackgroundBartels, M., Weckbecker, D., Kuhn, P., Ryazanov, S., Leonov, A., Griesinger, C., Lichtenthaler, S. F., Bötzel, K., & Giese, A. (2019) · Scientific Reports · doi:10.1038/s41598-019-45298-6 · Cited by 14
Ugalde, C. L., Gordon, S. E., Shambrook, M., Kenari, A. N., Coleman, B. M., Perugini, M. A., Lawson, V., Finkelstein, D. I., & Hill, A. F. (2020) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12034 · Cited by 14
Tinku, Paithankar, H., Rane, A. R., Hosur, R. V., & Choudhary, S. (2021) · Journal of Molecular Liquids · doi:10.1016/j.molliq.2021.116105 · Cited by 14
Medina, C. A., Vargas, E., Munger, S. J., & Miller, J. E. (2022) · PLoS ONE · doi:10.1371/journal.pone.0265604 · Cited by 15
Structural and Biophysical Characterization of Stable Alpha-Synuclein Oligomers
Vaikath, N. N., Sudhakaran, I. P., Abdi, I. Y., Gupta, V. R., Majbour, N. K., Ghanem, S. S., Abdesselem, H., Vekrellis, K., & El‐Agnaf, O. M. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232314630 · Cited by 14
“This is in accordance with the previous reports where they found that monomeric α-syn behaves like a large protein of ~50–60 kDa when assessed by non-denaturing techniques including size exclusion chromatography and native-PAGE gels [34].”
ResultATP13A2 and Alpha-synuclein: a Metal Taste in Autophagy
da Fonseca, T. L., & Outeiro, T. F. (2014) · Experimental Neurobiology · doi:10.5607/en.2014.23.4.314 · Cited by 14
“While the protein was initially thought to be natively unfolded and monomeric, recent studies proposed it may also adopt a tetrameric structure [7, 8].”
BackgroundMore than a Rumor Spreads in Parkinson's Disease
Prymaczok, N. C., Riek, R., & Gerez, J. (2016) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2016.00608 · Cited by 15
“Although still a matter of extensive debate, an emerging consensus indicates that within healthy cells αSyn exists as soluble low molecular weight species that play important roles in intra and extracellular vesicle trafficking and dynamics (Burre et al., 2010; Bartels et al., 2011; Fauvet et al., 2012; Theillet et al…”
BackgroundMiotto, M., Pavese, M. D., Quintanar, L., Zweckstetter, M., Griesinger, C., & Fernández, C. O. (2017) · Inorganic Chemistry · doi:10.1021/acs.inorgchem.7b01292 · Cited by 14
Xylaki, M., Boumpoureka, I., Kokotou, M. G., Marras, T., Papadimitriou, G., Kloukina, I., Magrioti, V., Kokotos, G., Vekrellis, K., & Emmanouilidou, E. (2020) · The FASEB Journal · doi:10.1096/fj.202001344r · Cited by 15
Functionalization of α-synuclein fibrils
Povilonienė, S., Časaitė, V., Bukauskas, V., Šetkus, A., Staniulis, J., & Meškys, R. (2015) · Beilstein Journal of Nanotechnology · doi:10.3762/bjnano.6.12 · Cited by 15
Parkinson disease is a fatty acidopathy
Fanning, S., & Selkoe, D. J. (2025) · Nature Reviews Neurology · doi:10.1038/s41582-025-01142-2 · Cited by 18
“Destabilization of tetramers with age or in PD and DLB is hypothesized to enable more monomers to accumulate, misfold and assemble into β-sheet-rich aggregates 111,113–116 .”
Self-citationJeacock, K., Chappard, A., Gallagher, K. J., Mackay, C. L., Kilgour, D. P. A., Horrocks, M. H., Kunath, T., & Clarke, D. J. (2023) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.2c00339 · Cited by 14
Folding of N-terminally acetylated α-synuclein upon interaction with lipid membranes
Tang, Z., Fang, Z., Wu, X., Liu, J., Tian, L., Li, X., Diao, J., Ji, B., & Li, D. (2024) · Biophysical Journal · doi:10.1016/j.bpj.2024.09.019 · Cited by 12
Yu, Y., Shen, H., Qin, Q., Wang, J., Nie, Y., Wen, L., Tang, Y., & Qu, M. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2024.12.057 · Cited by 13
Nam, M., Han, J.-H., Jang, J.-Y., Yun, S.-E., Kim, G.-Y., Kang, S., & Rhim, H. (2015) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2015.09.006 · Cited by 13
A pre-structured helix in the intrinsically disordered 4EBP1
Kim, D.-H., Lee, C., Cho, Y., Lee, S., Cha, E., Lim, J.-E., Sabo, T. M., Griesinger, C., Lee, D., & Han, K. (2014) · Molecular BioSystems · doi:10.1039/c4mb00532e · Cited by 13
Bédard, L., Lefèvre, T., Morin-Michaud, É., & Auger, M. (2014) · Biochemistry · doi:10.1021/bi5008707 · Cited by 13
Oh, Y. (2019) · BMB Reports · doi:10.5483/bmbrep.2019.52.6.142 · Cited by 13
“monomer, and rarely this tetramer is converted into the pathological aggregates (23, 24).”
BackgroundNavigating α‐Synuclein Aggregation Inhibition: Methods, Mechanisms, and Molecular Targets
Galkin, M., Priss, A., Kyriukha, Y. A., & Shvadchak, V. V. (2023) · The Chemical Record · doi:10.1002/tcr.202300282 · Cited by 14
Pratt, M. R., Abeywardana, T., & Marotta, N. P. (2015) · Biomolecules · doi:10.3390/biom5031210 · Cited by 14
Abdullah, R., Patil, K. S., Rosen, B., Pal, R., Prabhudesai, S. N., Lee, S., Basak, I., Hoedt, E., Yang, P. H., Panick, K., et al. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0266-8 · Cited by 14
Membrane remodeling by amyloidogenic and non-amyloidogenic proteins studied by EPR
Varkey, J., & Langen, R. (2017) · Journal of Magnetic Resonance · doi:10.1016/j.jmr.2017.02.014 · Cited by 13
“Recent reports showed that α-synuclein could also exist as a tetramer in the native conformation, adding to the list of already debated conformations [63, 64].”
BackgroundTorre-Muruzabal, T., Devoght, J., den Haute, C. V., Brône, B., der Perren, A. V., & Baekelandt, V. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0814-3 · Cited by 13
Computational prediction and redesign of aberrant protein oligomerization
Santos, J., Iglesias, V., & Ventura, S. (2019) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2019.11.002 · Cited by 13
Aspholm, E. E., Matečko‐Burmann, I., & Burmann, B. M. (2020) · Life · doi:10.3390/life10110289 · Cited by 13
“Interestingly, within mammalian cells, α-synuclein predominantly exists as an amino-terminally acetylated form as the physiologically relevant species [56,60].”
BackgroundMirau, P. A., Farmer, B. L., & Pandey, R. B. (2015) · AIP Advances · doi:10.1063/1.4927544 · Cited by 13
Sukhanova, A. V., Poly, S., Shemetov, A. A., Bronstein, I. B., & Nabiev, I. R. (2012) · Biopolymers · doi:10.1002/bip.22055 · Cited by 14
Clearance Pathways for α‐Synuclein in Parkinson's Disease
Ho, M. S.-C. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70124 · Cited by 16
α-synuclein in Parkinson’s disease: a central point of convergence with depression
Yusuf, A. M., İlçe, B. Y., Alhaj, H. A., & Hamoudi, R. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-01167-w · Cited by 12
Nuber, S., Zhang, X., McCaffery, T. D., Moors, T. E., Adom, M.-A., Hahn, W. N., Martin, D., Ericsson, M., Tripathi, A., Dettmer, U., et al. (2024) · npj Parkinson s Disease · doi:10.1038/s41531-024-00662-w · Cited by 13
Self-citationAggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson’s patients
de Boni, L., Wallis, A., Watson, A. H., Ruiz‐Riquelme, A., Leyland, L., Bourinaris, T., Hannaway, N., Wüllner, U., Peters, O., Priller, J., et al. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00083-5 · Cited by 13
“2A and EV1A) besides other minor multimeric bands, as described previously for blood and red blood cells (Bartels et al, 2011).”
BackgroundInfluentialSelf-citationTripathi, N., Saudrais, F., Rysak, M., Pieri, L., Pin, S., Roma, G., Renault, J., & Boulard, Y. (2024) · Biomacromolecules · doi:10.1021/acs.biomac.4c00918 · Cited by 12
Structural basis of a distinct α-synuclein strain that promotes tau inclusion in neurons
Sun, C., Zhou, K., DePaola, P., Li, C., Lee, V. M. ‐., Zhou, Z. H., Peng, C., & Jiang, L. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.108351 · Cited by 12
“Under physiological conditions, a -syn exists as a natively unfolded monomer or an a -helical tetramer (7).”
Surface wetting is a key determinant of α-synuclein condensate maturation
Thrush, R. J., Vadukul, D. M., Allerton, S. C., Storch, M., & Aprile, F. A. (2025) · Communications Chemistry · doi:10.1038/s42004-025-01764-z · Cited by 13
“7,8 The aberrant accumulation of α-syn amyloid fibrils is the major hallmark of neurodegenerative diseases including Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy.”
Alderson, T. R., & Bax, A. (2016) · Nature · doi:10.1038/nature16871 · Cited by 12
Acetylation of Aβ 40 Alters Aggregation in the Presence and Absence of Lipid Membranes
Pilkington, A. W., Schupp, J. E., Nyman, M., Valentine, S. J., Smith, D. M., & Legleiter, J. A. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00483 · Cited by 12
Shim, K. H., Kim, S. C., Youn, Y. C., Sung, Y. H., & An, S. S. A. (2020) · Molecular & Cellular Toxicology · doi:10.1007/s13273-020-00104-7 · Cited by 11
α-Synuclein and neuronal membranes: Conformational flexibilities in health and disease
Bozelli, J. C., Kamski‐Hennekam, E. R., Melacini, G., & Epand, R. M. (2021) · Chemistry and Physics of Lipids · doi:10.1016/j.chemphyslip.2020.105034 · Cited by 13
Mirdha, L., & Chakraborty, H. (2021) · European Biophysics Journal · doi:10.1007/s00249-021-01505-9 · Cited by 12
The Strategies of Development of New Non-Toxic Inhibitors of Amyloid Formation
Galzitskaya, O. V., Grishin, S. Y., Glyakina, A. V., Dovidchenko, N. V., Konstantinova, A. V., Kravchenko, S. V., & Surin, A. K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043781 · Cited by 12
Research Progress of α-Synuclein Aggregation Inhibitors for Potential Parkinson’s Disease Treatment
Kalsoom, I., Wang, Y., Li, B., & Wen, H. (2023) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/1389557523666230517163501 · Cited by 14
GM1 oligosaccharide efficacy against α-synuclein aggregation and toxicity in vitro
Fazzari, M., Biase, E. D., Zaccagnini, L., Henriques, A., Callizot, N., Ciampa, M. G., Mauri, L., Carsana, E. V., Loberto, N., Aureli, M., et al. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2023.159350 · Cited by 12
Self-citationReed, A. L., Mitchell, W., Alexandrescu, A. T., & Alder, N. N. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1263420 · Cited by 13
Glutamine promotes Hsp70 and inhibits α-Synuclein accumulation in pheochromocytoma PC12 cells
Wang, H., Tang, C., Jiang, Z., Zhou, X., Chen, J., Meng, N., Shen, H., & Lin, Z. (2017) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2017.4580 · Cited by 12
“…the dorsal motor nucleus of the vagus (3-5). α -Syn belongs to a family of structurally associated proteins in the brain (6,7), which serve an important role in neurotransmitter release (8) by promoting the assembly of the soluble N-ethylmaleimide-sensitive fusion attachment protein machinery (9).”
Progress in the treatment of Parkinson-Plus syndromes
Olfati, N., Shoeibi, A., & Litvan, I. (2018) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2018.10.006 · Cited by 16
Studying α-Synuclein Conformation by Intact-Cell Cross-Linking
Imberdis, T., Fanning, S., Newman, A. J., Ramalingam, N., & Dettmer, U. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9124-2_8 · Cited by 11
“Janus-Faced” α-Synuclein: Role in Parkinson’s Disease
Ray, B., Mahalakshmi, A. M., Tuladhar, S., Bhat, A., Srinivasan, A., Pellegrino, C., Kannan, A., Bolla, S. R., Chidambaram, S. B., & Sakharkar, M. K. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.673395 · Cited by 14
“Under physiological conditions, native α-syn has a tendency to remain folded (Bartels et al., 2011; Wang et al., 2011).”
BackgroundInfluentialStokholm, K., Thomsen, M. B., Phan, J.-A., Møller, L. K., Bay-Richter, C., Christiansen, S. H., Woldbye, D. P. D., Romero‐Ramos, M., & Landau, A. M. (2021) · Biomedicines · doi:10.3390/biomedicines9121876 · Cited by 13
“In a healthy brain, ASYN is present as a soluble unfolded monomer or helically folded tetramer [2,3], but during PD, ASYN aggregates and forms intraneuronal Lewy bodies and neurites [4–6].”
BackgroundYang, J. Y., Zhang, Y., ZHAO, S., ZHANG, Z., TONG, X., Wei, F., & Lu, Z. (2015) · Molecular Medicine Reports · doi:10.3892/mmr.2015.4027 · Cited by 12
“…highly expressed at pre-synaptic terminals and promotes the assembly of the SNARE machinery (10), with an importance for neurotransmitter release (11) and the protection of nerve terminals against injury (12). α -Syn has been widely accepted to have a natively unfolded tertiary structure as its…”
α-Synuclein in Parkinson's Disease: 12 Years LaterPreprint
Vekrellis, K., Emmanouilidou, E., Xilouri, M., & Stefanis, L. (2024) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041645 · Cited by 14
Pieger, K., Schmitt, V., Gauer, C., Gießl, N., Prots, I., Winner, B., Winkler, J., Brandstätter, J. H., & Xiang, W. (2022) · Biomolecules · doi:10.3390/biom12081108 · Cited by 11
α-Synuclein-dependent increases in PIP5K1γ drive inositol signaling to promote neurotoxicity
Horvath, J. D., Casas, M., Kutchukian, C., Sánchez, S. C., Pergande, M. R., Cologna, S. M., Simó, S., Dixon, R. E., & Dickson, E. J. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113244 · Cited by 11
“…-Syn accumulation in synucleinopathies (for model, see Figure S5). α -Syn is an intrinsically disordered protein that exists in a variety of conformations, with the prevailing, but not universal, 29,87,88 hypothesis positing that its cumulative oligomerization at membranes correlates with toxicity.”
BackgroundA-Syn(ful) MAM: A Fresh Perspective on a Converging Domain in Parkinson’s Disease
Barbuti, P. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126525 · Cited by 12
“The non-amyloid-β component (NAC) domain (residues 61–95) is a hydrophobic central domain that is required for nucleation of the aggregation process [25].”
Backgroundβ-Synuclein Intermediates α-Synuclein Neurotoxicity in Parkinson’s Disease
Xian, M., Li, J., Liu, T., Hou, K., Sun, L., & Wei, J. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.4c00263 · Cited by 11
Li, K., Ling, H., Huang, W., Luo, W., Gu, C., Tao, B., Xie, Q., & Qiu, P. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112676 · Cited by 11
Milos, T., Vuić, B., Balic, N., Farkaš, V., Erjavec, G. N., Štrac, D. Š., Perković, M. N., & Pivac, N. (2024) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2024.2400683 · Cited by 11
“It is encoded by SNCA gene and normally, it can exist in two forms, as unfolded monomer or as a folded tetramer of about 58 KDa [195].”
Navigating the Neurobiology of Parkinson’s: The Impact and Potential of α-Synuclein
Paulėkas, E., Vanagas, T., Lagunavičius, S., Pajėdienė, E., Petrikonis, K., & Rastenytė, D. (2024) · Biomedicines · doi:10.3390/biomedicines12092121 · Cited by 12
Khan, M. A. (2025) · Biomolecules · doi:10.3390/biom15020214 · Cited by 12
“Endogenous α -Syn has long been believed to be a naturally unfolded monomer; however, it has been demonstrated to occur mostly as a folded tetramer with little to no amyloid-like accumulation potential [18].”
Kragelj, J., Ghosh, R., Xiao, Y., Dumarieh, R., Lagasca, D., Krishna, S., & Frederick, K. K. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2500367122 · Cited by 11
Epigenetic mechanisms linking environmental exposure to Parkinson’s disease: A comprehensive review
Singh, H., Kumari, S., & Taliyan, R. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.08.060 · Cited by 14
Cahill, C. M., Aleyadeh, R., Gao, J., Wang, C., & Rogers, J. T. (2020) · Biomolecules · doi:10.3390/biom10101465 · Cited by 11
“Bartels and colleagues have shown that endogenous α-Syn mainly occurs as a folded tetramer of about 58 kDa, which interacts by means of its central helices [71].”
BackgroundZijlstra, N., Blum, C., Segers‐Nolten, I. M. J., Claessens, M. M. A. E., & Subramaniam, V. (2012) · Angewandte Chemie · doi:10.1002/ange.201200813 · Cited by 11
Saurabh, A., & Prabhu, N. P. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.11.079 · Cited by 11
Bhopatkar, A. A., Bhatt, N. N., Haque, M. A., Xavier, R., Fung, L., Jerez, C., & Kayed, R. (2024) · Protein Science · doi:10.1002/pro.5099 · Cited by 9
“Both of these structural elements are commonly adopted by soluble oligomers of other proteins as well (Bartels et al., 2011; Cerf et al., 2009; Tew et al., 2008; Zacco et al., 2018; Zou et al., 2013), and both are purportedly responsible for inducing toxicity by disrupting cellular membranes (Cerf…”
BackgroundThe role of transcriptional control in multiple system atrophy
Chen, J., Mills, J. D., Halliday, G. M., & Janitz, M. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.08.015 · Cited by 11
Killinger, B. A., & Moszczyńska, A. (2016) · Analytical Chemistry · doi:10.1021/acs.analchem.6b00419 · Cited by 11
The Mechanism of p53 Rescue by SUSP4
Kim, D., Lee, C., Lee, S., Kim, K., Han, J. J., Cha, E., Lim, J., Cho, Y., Hong, S., & Han, K. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201607819 · Cited by 11
Modulation of α-Synuclein Aggregation by Cytochrome c Binding and Hetero-dityrosine Adduct Formation
Ghosh, S. K., Mahapatra, A., & Chattopadhyay, K. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00393 · Cited by 11
Evans, S. R., West, C., & Klein‐Seetharaman, J. (2021) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2021.09.011 · Cited by 10
“There is also evidence of the stable tetrameric structure in human erythrocytes and neurons [4,20,21], and the tetramer is proposed to exist in metastable equilibrium with the unfolded monomer [6].”
BackgroundGadhavi, J. D., Patel, M., Bhatia, D. D., & Gupta, S. K. (2021) · Biochimie · doi:10.1016/j.biochi.2021.09.012 · Cited by 11
Integrated control of protein degradation in C. elegans muscle
Lehmann, S., Shephard, F., Jacobson, L. A., & Szewczyk, N. J. (2012) · Worm · doi:10.4161/worm.20465 · Cited by 11
Hashimoto, M., & Spada, A. R. L. (2012) · Future Neurology · doi:10.2217/fnl.12.5 · Cited by 11
Plotnick, L., Rapaport, R., Desrosiers, P., & Fuqua, J. S. (2009) · PubMed · Cited by 11
Levels of α‐ and β‐synuclein regulate cellular susceptibility to toxicity from α‐synuclein oligomers
Angelova, D. M., Jones, H. B. L., & Brown, D. R. (2017) · The FASEB Journal · doi:10.1096/fj.201700675r · Cited by 12
“Both synucleins are able to formdimers and tetramers (83, 84), and the latter is believed to be the correct form for cellulara-syn.”
BackgroundAn N-terminal alpha-synuclein fragment binds lipid vesicles to modulate lipid-induced aggregation
Meade, R. M., Allen, S. G., Williams, C., Tang, T. M. S., Crump, M. P., & Mason, J. M. (2023) · Cell Reports Physical Science · doi:10.1016/j.xcrp.2023.101563 · Cited by 10
Sanluca, C., Spagnolo, P., Mancinelli, R., Bartolo, M. I. D., Fava, M., Maccarrone, M., Carotti, S., Gaudio, E., Leuti, A., & Vivacqua, G. (2024) · Metabolites · doi:10.3390/metabo14070352 · Cited by 9
“…monomer that acquires an alpha-helical secondary structure when interacting with lipids membranes [44], it was recently suggested that native α -Syn exists physiologically as a folded helical tetramer that is resistant to fibrillization and is thus distinct from pathological oligomers [45–48].”
BackgroundMinimal Nucleation State of α-Synuclein Is Stabilized by Dynamic Threonine–Water Networks
Romo, T. D., Lewis, A. K., Braun, A. R., Grossfield, A. M., & Sachs, J. N. (2017) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.7b00171 · Cited by 10
Targeting α-Synuclein in Parkinson's Disease by Induced Pluripotent Stem Cell Models
Spathopoulou, A., Edenhofer, F., & Fellner, L. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2021.786835 · Cited by 10
Beyond neurodegenerative diseases: α-synuclein in erythropoiesis
Ling, L., Wang, F., & Yu, D. (2022) · Hematology · doi:10.1080/16078454.2022.2078041 · Cited by 11
“[30,31], yet other follow-up studies support that αsyn exists mainly in the form of unfolded monomer [32–34].”
BackgroundPost-translational modification of lysine residues in erythrocyte α-synuclein
Amagai, R., Yoshioka, S., Otomo, R., Nagano, H., Hashimoto, N., Sakakibara, R., Tanaka, T., & Okado‐Matsumoto, A. (2022) · The Journal of Biochemistry · doi:10.1093/jb/mvac100 · Cited by 10
Induced Pluripotent Stem Cell-Based Studies of Parkinson's Disease: Challenges and Promises
Sánchez‐Danés, A., Benzoni, P., Memo, M., Dell`Era, P., Raya, Á., & Consiglio, A. (2013) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152731131200128 · Cited by 11
Hecel, A., Ricco, R. D., & Valensin, D. (2016) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2016.06.018 · Cited by 10
Mejía, M., Rodríguez‐Leyva, I., Cortés-Enríquez, F., Chi-Ahumada, É., Portales‐Pérez, D. P., Macías-Islas, M. Á., & Jiménez-Capdeville, M. E. (2018) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2018.11.003 · Cited by 11
Tian, Y., Stanyon, H. F., Barritt, J. D., Mayet, U., Patel, P., Karamani, E., Fusco, G., & Viles, J. H. (2019) · Inorganic Chemistry · doi:10.1021/acs.inorgchem.9b02644 · Cited by 10
Triple-Knockout, Synuclein-Free Mice Display Compromised Lipid Pattern
Guschina, I. A., Ninkina, N. N., Roman, A. Y., Pokrovskiy, M. V., & Buchman, V. L. (2021) · Molecules · doi:10.3390/molecules26113078 · Cited by 10
“Either monomeric form of α-synuclein or the formation of α – helically folded tetramers and related multimers has been demonstrated [24, 27, 28, 29, 30, 31].”
BackgroundIwabuchi, M., Hetu, M. M., & Tong, W. G. (2016) · Analytical Biochemistry · doi:10.1016/j.ab.2016.01.010 · Cited by 10
Jacob, R. S., Dema, A., Chérot, H., Dumesnil, C., Cohen, S., Shalom, H. S., Rimon, N., Sibony-Nevo, O., Beck, G., Ainbinder, E., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.19.599670 · Cited by 11
Harris, P. D., & Lerner, E. (2022) · Biophysical Reports · doi:10.1016/j.bpr.2022.100071 · Cited by 9
The role of Nα‐terminal acetylation in protein conformation
Calis, S., & Gevaert, K. (2024) · FEBS Journal · doi:10.1111/febs.17209 · Cited by 9
“[68] provided the first evidence that endogenous, N a -terminally acetylated a S, isolated from diverse human cell lines and clinical samples like human erythrocytes, partially exists as a folded tetramer of 58 kDa which exhibits greatly reduced aggregation kinetics [67].”
Fu, C., Yang, N., Chuang, J.-Z., Nakajima, N., Iraha, S., Roy, N. S., Wu, Z., Jiang, Z., Otsu, W., Radu, R. A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50189-0 · Cited by 9
“Emerging data revealed α Syn is physiologically folded as tetramers 108,113 – 115 whereas α Syn dimers have been linked to oxidative stress 116 .”
β-synuclein blocks α-synuclein condensate fusion to disrupt the maturation of phase separation
Xu, B., He, W., Fan, F., Chen, S., Zhu, M., Hou, Y., Zheng, L., Yu, H., & Liu, Y. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115761 · Cited by 9
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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