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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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“In 2011, two groups reported that cellular α-Syn exists as a helical tetramer when purified under non-denaturing conditions [10, 11].”
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“Compared to aggregation-prone monomeric forms, α -Syn tetramers exhibit little or no amyloid-like aggregation potential 10 .”
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BackgroundExploring Structural Flexibility and Stability of α-Synuclein by the Landau–Ginzburg–Wilson Approach
Korneev, A., Begun, A. M., Liubimov, S. D., Kachlishvili, K., Molochkov, A. V., Niemi, A. J., & Maisuradze, G. G. (2022) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.2c04651 · Cited by 6
Parkinson’s Disease: Basic Pathomechanisms and a Clinical Overview
Noyce, A. J., & Bandopadhyay, R. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-57193-5_3 · Cited by 7
Bézard, E., & Dehay, B. (2022) · médecine/sciences · doi:10.1051/medsci/2021241 · Cited by 15
Wang, X., Norgate, E., Dai, J., Benoit, F., Bristow, T., England, R. M., Kalapothakis, J. M. D., & Barran, P. E. (2025) · Nature Communications · doi:10.1038/s41467-025-59065-x · Cited by 7
“It has been suggested that α -synuclein may form a more stable helical structure in a highly hydrophobic environment 63,66,67 .”
Abioye, A. O., Akintade, D. D., Mitchell, J., Olorode, S., & Adejare, A. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16050609 · Cited by 7
Conformational Selection of α-Synuclein Tetramers at Biological Interfaces
Bhattacharya, S., Xu, L., Arrué, L., Bartels, T., & Thompson, D. (2024) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.4c01459 · Cited by 6
“57 − 61 Control simulations of a completely disordered tetramer on the POPS membrane (Figure S19) showed negligible interactions and contacts between the unstructured tetramer and the membrane, while only a small population (2”
Self-citationN-terminal acetylation does not alter α-synuclein's interfacial properties
Mohapatra, A., & Chaudhary, N. (2021) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2021.01.147 · Cited by 5
Taha, H. B., Chawla, E., & Bitan, G. (2023) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.3c00065 · Cited by 4
Das, D., Bharadwaz, P., & Mattaparthi, V. S. K. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2023.2262599 · Cited by 5
“Oligomers of varied sizes have been suggested to be harmful in certain investigations, whereas greater molecular weight aggregates have been suggested in other studies (Bucciantini et al., 2002; Bartels et al., 2011; Conway et al., 2000; Cremades et al., 2012).”
Kon, T., Lee, S., Martínez-Valbuena, I., Yoshida, K., Tanikawa, S., Lang, A. E., & Kovács, G. G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052676 · Cited by 5
Jamerlan, A., Shim, K. H., Sharma, N., & An, S. S. A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26031199 · Cited by 5
Showing transmitters the door: synucleins accelerate vesicle release
Selkoe, D. J. (2017) · Nature Neuroscience · doi:10.1038/nn.4551 · Cited by 5
Self-citationde Oliveira, G. A. P., Marques, M. A., Pedrote, M. M., & Silva, J. L. (2019) · High Pressure Research · doi:10.1080/08957959.2019.1576173 · Cited by 5
The Alzheimer–E. coli Axis: What Can We Learn from an Electronic Health Record Platform
Katz, J., & Gao, H. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-215004 · Cited by 5
“-synuclein deposition in both gut and brain and enhanced microgliosis and astrogliosis [10].”
Nutrient‐sensing amyloid metastasis
Lima, L. M. T. R., & Sisnande, T. (2022) · BioFactors · doi:10.1002/biof.1825 · Cited by 5
“Indeed, αSyn is naturally unfolded peptide,(223,224) exhibits a high affinity with transition metals,225–227 and the native protein forms a stable tetramer resistant to aggregation.(228) αSyn affinity with metals is variable(229) and the morphology of fibrils changes accordingly the ligand.”
BackgroundImmunotherapeutic interventions in Parkinson's disease: Focus on α-Synuclein
Ganguly, U., Singh, S., Chakrabarti, S., Saini, A. K., & Saini, R. V. (2022) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2021.11.010 · Cited by 6
Computational investigation of copper-mediated conformational changes in α-synuclein dimer
Savva, L., & Platts, J. A. (2024) · Physical Chemistry Chemical Physics · doi:10.1039/d3cp04697d · Cited by 5
“21 Concerning the aggregation of biomolecular systems, one usually looks for a nucleation– elongation process, 22 with the off-pathway formation of amorphous aggregates, found to decrease the development of fibrils.”
The native form of α‐Synuclein: Monomer, tetramer, or a combination in equilibrium
Corbett, G. T., & Kordower, J. H. (2015) · Movement Disorders · doi:10.1002/mds.26361 · Cited by 5
A Rapid, Semi-Quantitative Assay to Screen for Modulators of Alpha-Synuclein Oligomerization Ex vivo
Delenclos, M., Trendafilova, T., Jones, D. R., Moussaud, S., Baine, A.-M. T., Yue, M., Hirst, W. D., & McLean, P. J. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00511 · Cited by 5
“Normally, αsyn is a soluble, presynaptic protein that may exist as a natively unfolded monomer or a functional tetramer (Bartels et al., 2011; Wang et al., 2011; Fauvet et al., 2012; Burré et al., 2013; Gurry et al., 2013; Selkoe et al., 2014; Dettmer et al., 2015a,b).”
BackgroundKelley, A. R., Colley, M. E., Perry, G. L., & Bach, S. B. H. (2017) · Journal of Mass Spectrometry · doi:10.1002/jms.4044 · Cited by 4
Jadavi, S., Canepa, E., Diaspro, A., Canale, C., Relini, A., & Dante, S. (2021) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2021.183814 · Cited by 4
Dey, M., Gupta, A., Badmalia, M. D., Ashish, & Sharma, D. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.138614 · Cited by 5
Astrocyte alterations in α-synucleinopathies
Rodríguez-Castañeda, M., Campos-Ríos, A., Lamas, J. A., & Covelo, A. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1650326 · Cited by 5
Giussani, P., Mauri, L., & Sonnino, S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262211118 · Cited by 7
“GM1 stabilizes the non-amyloidogenic α -helix conformation of the protein, strongly interacting with α -synuclein [185,186,195], thus exerting a neuroprotective effect.”
Mori, F., Nakamura, Y., Miki, Y., Tanji, K., Kon, T., Tomiyama, M., Kakita, A., & Wakabayashi, K. (2022) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlac070 · Cited by 4
Gatzemeier, L. M., Meyer, F., & Outeiro, T. F. (2024) · ChemBioChem · doi:10.1002/cbic.202400253 · Cited by 3
Is the Voltage-Dependent Anion Channel a Major Player in Neurodegenerative Diseases?
Neumann, S., & Heumann, R. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26136138 · Cited by 5
“The phosphorylation of α Syn at S129 influences the interaction between α Syn and lipid membrane and strengthens its binding to metal ions and further proteins, resulting in protein aggregation [208].”
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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