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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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“Recent data suggested that AS isolated from neuronal and non-neuronal cell lines exists predominantly as a putative tetramer that is rich in a-helices [75].”
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Self-citationClinical biomarkers for Lewy body diseases
Abdelmoaty, M. M., Lu, E., Kadry, R., Foster, E. G., Bhattarai, S., Mosley, R. L., & Gendelman, H. E. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01152-x · Cited by 17
“…α-Syn is a small acidic protein expressed in the CNS, peripheral nervous system (PNS), blood, and other tissues [121]. α-Syn is natively unfolded monomer, however it is found naturally, in large part, as a folded tetramer of 58 KDa with little or no amyloid-like aggregation potential [122].”
BackgroundZalon, A. J., Quiriconi, D. J., Pitcairn, C., & Mazzulli, J. R. (2024) · The Neuroscientist · doi:10.1177/10738584241232963 · Cited by 16
α-Synuclein orchestrates Th17 responses as antigen and adjuvant in Parkinson’s disease
Furusawa-Nishii, E., Солонго, Б., Rai, K., Yoshikawa, S., Chiba, A., Okuzumi, A., Ueno, S., Hoshino, Y., Imamichi, Y., Kimura, H., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03359-w · Cited by 18
“…loss of motor and/or cognitive functions accompanied by abnormal α-synuclein (αS) deposition. αS usually exists as a nontoxic monomer or tetramer [10, 11]; however, in brain regions affected by synucleinopa-thies, the αS structure changes from nontoxic monomers to toxic oligomers or fibrils.”
Fernández‐Espejo, E., García-Moreno, J., de Pablos, Á. M., & Chacón, J. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6072 · Cited by 16
“An *56 kDa band is characteristic of tetrameric a-synuclein (1).”
The N-terminal Helix Controls the Transition between the Soluble and Amyloid States of an FF Domain
Castillo, V., Chiti, F., & Ventura, S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0058297 · Cited by 16
Prion-like propagation of α-synuclein in the gut-brain axis
Chen, Y., Shao, Q.-H., Yuan, Y., & Chen, N. (2018) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2018.06.002 · Cited by 15
Camilloni, C., & Vendruscolo, M. (2013) · The Journal of Physical Chemistry B · doi:10.1021/jp405614j · Cited by 14
α-Synuclein in traumatic and vascular diseases of the central nervous system
Zeng, H., Liu, N., Liu, X.-X., Yang, Y., & Zhou, M. (2020) · Aging · doi:10.18632/aging.103675 · Cited by 17
“Tetramer can maintain α-Syn steady state and resist aggregation [7].”
BackgroundWeston, L. J., Bowman, A. M., Osterberg, V. R., Meshul, C. K., Woltjer, R. L., & Unni, V. K. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315294 · Cited by 16
“aSyn is stable in a monomeric or potentially tetrameric conformation [2,3]; however, it can form pathological intracellular aggregates that are tightly associated with a group of neurodegenerative diseases often known as synucleinopathies.”
BackgroundUnderstanding the dynamics of monomeric, dimeric, and tetrameric α‐synuclein structures in water
Mane, J. Y., & Stepanova, M. (2016) · FEBS Open Bio · doi:10.1002/2211-5463.12069 · Cited by 15
Choi, J., Polcher, A. A., & Joas, A. (2016) · EFSA Supporting Publications · doi:10.2903/sp.efsa.2016.en-955 · Cited by 18
Self-citationDo, H. Q., Hewetson, A., Myers, C., Khan, N. H., Hastert, M. C., Harsini, F. M., Latham, M. P., Wylie, B. J., Sutton, R. B., & Cornwall, G. A. (2019) · Scientific Reports · doi:10.1038/s41598-019-45545-w · Cited by 15
Masaracchia, C., König, A., Valiente‐Gabioud, A. A., Peralta, P., Favretto, F., Strohäker, T., Lázaro, D. F., Zweckstetter, M., Fernández, C. O., & Outeiro, T. F. (2019) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2019.140298 · Cited by 15
Optimizing red blood cell protein extraction for biomarker quantitation with mass spectrometry
Klatt, S., Roberts, A. M., Lothian, A., Masters, C. L., Cappai, R., Fowler, C. J., & Roberts, B. R. (2020) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-020-02439-5 · Cited by 15
Parkinson’s Disease: Is there a Role for Dietary and Herbal Supplements?
Onaolapo, O. J., Odeniyi, A. O., & Onaolapo, A. Y. (2021) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527320666210218082954 · Cited by 15
Role of VAPB and vesicular profiles in α‐synuclein aggregates in multiple system atrophy
Mori, F., Miki, Y., Tanji, K., Kon, T., Tomiyama, M., Kakita, A., & Wakabayashi, K. (2021) · Brain Pathology · doi:10.1111/bpa.13001 · Cited by 14
“α- Syn can bind to lipid membranes to perform physiological functions (20) or form a tetramer with an αhelical structure that can resist abnormal aggregation (21).”
Kim, T., Newman, A. J., Imberdis, T., Brontesi, L., Tripathi, A., Ramalingam, N., Fanning, S., Selkoe, D. J., & Dettmer, U. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddab188 · Cited by 17
“Of note, it has been suggested that native αS multimerization is a cellular mechanism of preventing αS aggregation (28).”
BackgroundSelf-citationInvestigation of Intramolecular Dynamics and Conformations of α-, β- and γ-Synuclein
Ducas, V. C., & Rhoades, E. R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0086983 · Cited by 15
“The synucleins have also been found in various other cell types including liver (cS), skeletal muscle (aS, bS, and cS), lung (aS) and red blood (aS) cells [1,3].”
BackgroundCai, Z., Xu, J., Xue, S.-R., Liu, Y.-Y., Zhang, Y., Zhang, X.-Z., Wang, X., Wu, F., & Li, X. (2015) · Neural Regeneration Research · doi:10.4103/1673-5374.162763 · Cited by 15
“Accumulating evidence shows that α-synuclein misfolding, aggregation and abnormal degradation cause dopaminergic neuron death (Bartels et al., 2011; Gadad et al., 2011; Cremades et al., 2012).”
BackgroundMini review: linkage between α-Synuclein protein and cognition
Saleh, H., Saleh, A. A., Yao, H., Cui, J., Shen, Y., & Li, R. (2015) · Translational Neurodegeneration · doi:10.1186/s40035-015-0026-0 · Cited by 15
Menéndez‐González, M., Padilla-Zambrano, H., Tomás‐Zapico, C., & Fernández‐Garcia, B. (2018) · Brain Sciences · doi:10.3390/brainsci8040052 · Cited by 15
“observed the status of endogenous α-Syn in human red blood cells, showing that this endogenous cellular protein exists natively as a 58 kDa helically folded tetramer [13].”
BackgroundErythrocytes as Biomarkers for Dementia: Analysis of Protein Content and Alpha-Synuclein
Graham, C., Santiago-Mujika, E., Abdel‐All, Z., Li, M., McNally, R., Kalaria, R. N., & Mukaetova‐Ladinska, E. B. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190567 · Cited by 15
“A previous study demonstrated that the AS tetramer is the main AS species found in the human ERC, which, therefore, explains the presence of the tetramer but no other oligomer, within the control subjects [29].”
InfluentialTira, R., Cecco, E. D., Rigamonti, V., Santambrogio, C., Barracchia, C. G., Munari, F., Romeo, A., Legname, G., Prosperi, D., Grandori, R., et al. (2020) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2020.03.118 · Cited by 15
Sinnige, T., Stroobants, K., Dobson, C. M., & Vendruscolo, M. (2020) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583520000025 · Cited by 18
“Recently, a mouse model was created following the hypothesis that native α-synuclein can occur as folded tetramers, such that a shift to the monomeric conformation puts the protein at risk of aggregation (Bartels et al., 2011; Dettmer et al., 2015).”
BackgroundSinnige, T., Stroobants, K., Dobson, C. M., & Vendruscolo, M. (2020) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583520000104 · Cited by 15
Byrd, E. J., Rowlinson, B., Crossley, J. A., Brockwell, D. J., Ross, J. F., Radford, S. E., & Sobott, F. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c11056 · Cited by 16
Deconvoluting the complexity of autophagy and Parkinson's disease for potential therapeutic purpose
Li, J., Li, S., Zhang, L., Ouyang, L., & Liu, B. (2015) · Oncotarget · doi:10.18632/oncotarget.5803 · Cited by 14
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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