Defining the Native State of α-Synuclein
Abstract
Misfolding and pathogenic aggregation of α-synuclein (αSyn) is a hallmark of familial and sporadic Parkinson's disease, but the physiological state of the protein in cells remains unsettled. We have further examined our hypothesis that endogenous αSyn can occur in normal cells as a metastable, helically folded tetramer, not solely as the unfolded monomer long thought to be its native form. At this meeting, we reviewed our recent approaches for trapping αSyn in intact cells via in vivo crosslinking, a 5-step purification of αSyn from normal human brain, and the generation of new monoclonal antibodies to αSyn that enable general and oligomer-selective ELISAs. Crosslinking in intact living cells confirmed that αSyn occurs in the cytosol of neurons and non-neural cells in substantial part as metastable tetramers and related oligomers, plus varying amounts of free monomers. The non-pathogenic homolog, β-synuclein, forms closely similar oligomeric assemblies, suggesting that the oligomers we observe for αSyn are also physiological. In contrast to other normal oligomeric proteins (e.g., DJ-1), αSyn tetramers dissociate rapidly to monomers upon conventional cell lysis but are retained partially as tetramers if cells are lysed at high protein concentrations (‘molecular crowding'). Thus, αSyn exists natively as helical tetramers that are in dynamic equilibrium with unfolded monomers. The tetramers appear relatively resistant to aggregation, in contrast to monomers, which may give rise to fibrillar inclusions.
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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 [140]
Cites
α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation
Bartels, T., Choi, J. G., & Selkoe, D. J. (2011) · Nature · doi:10.1038/nature10324 · Cited by 1,263 · see citing works
Self-citationFauvet, 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
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
Dettmer, 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
Self-citationYang, T., Hong, S. Y., O’Malley, T. T., Sperling, R. A., Walsh, D. M., & Selkoe, D. J. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2012.11.005 · Cited by 121 · see citing works
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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
Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease
George, S., Rey, N. L., Tyson, T., Esquibel, C., Meyerdirk, L., Schulz, E., Pierce, S., Burmeister, A. R., Madaj, Z., Steiner, J. A., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0335-3 · Cited by 229 · see citing works
Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits
Larson, M. E., Greimel, S. J., Amar, F., LaCroix, M., Boyle, G., Sherman, M. A., Schley, H., Miel, C., Schneider, J. A., Kayed, R., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1704698114 · Cited by 61 · see citing works
- Authors
- Selkoe, D., Dettmer, U., Luth, E., Kim, N., Newman, A., & Bartels, T.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- Neurodegenerative Diseases
- Publisher
- S. Karger AG
- Published
- 2013-10-30
- Volume
- 13
- Issue
- 2-3
- Pages
- 114-117
- ISSN
- 1660-2854 (ISSN-L)
- 1660-2862
- OpenAlex
- W2016718240
- Cited by
- 45
- References
- 5
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 4 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 5 · 2018: 5 · 2017: 4 · 2016: 5 · 2015: 5 · 2014: 4
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurodegenerative Diseases (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- alpha-synuclein, native state, protein oligomers, Parkinson's disease, protein misfolding, in vivo cross-linking, beta-synuclein, macromolecular crowding, oligomer dissociation, monoclonal antibodies, ELISA, human brain
- MeSH terms
- Animals, Brain, Humans, Parkinson Disease, alpha-Synuclein
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