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Regulation of α-synuclein by chaperones in mammalian cells
Open accessAbstract
Neurodegeneration in patients with Parkinson's disease is correlated with the occurrence of Lewy bodies-intracellular inclusions that contain aggregates of the intrinsically disordered protein α-synuclein 1. The aggregation propensity of α-synuclein in cells is modulated by specific factors that include post-translational modifications 2,3, Abelson-kinase-mediated phosphorylation 4,5 and interactions with intracellular machineries such as molecular chaperones, although the underlying mechanisms are unclear 6-8. Here we systematically characterize the interaction of molecular chaperones with α-synuclein in vitro as well as in cells at the atomic level. We find that six highly divergent molecular chaperones commonly recognize a canonical motif in α-synuclein, consisting of the N terminus and a segment around Tyr39, and hinder the aggregation of α-synuclein. NMR experiments 9 in cells show that the same transient interaction pattern is preserved inside living mammalian cells. Specific inhibition of the interactions between α-synuclein and the chaperone HSC70 and members of the HSP90 family, including HSP90β, results in transient membrane binding and triggers a remarkable re-localization of α-synuclein to the mitochondria and concomitant formation of aggregates. Phosphorylation of α-synuclein at Tyr39 directly impairs the interaction of α-synuclein with chaperones, thus providing a functional explanation for the role of Abelson kinase in Parkinson's disease. Our results establish a master regulatory mechanism of α-synuclein function and aggregation in mammalian cells, extending the functional repertoire of molecular chaperones and highlighting new perspectives for therapeutic interventions for Parkinson's disease.
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“This suggests that Hsp90 has a holdase function for these proteins by binding and protecting them from aggregation (69).”
From Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network (2021) · cites this paper as [69]
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Cites
Neurodegenerative diseases and oxidative stress
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Molecular Chaperone Functions in Protein Folding and Proteostasis
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Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes
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Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein
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Structural disorder of monomeric α-synuclein persists in mammalian cells
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Self-citationComposition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins
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Yao, Z., Li, H., Liao, P., Chen, L., Pan, Y., Zheng, Y., Zhang, C., Liu, D., Zheng, M., & Gao, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01839-8 · Cited by 1,382
Mechanisms and pathology of protein misfolding and aggregation
Louros, N. N., Schymkowitz, J. W. H., & Rousseau, F. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00647-2 · Cited by 271
Molecular dissection of amyloid disaggregation by human HSP70
Wentink, A. S., Nillegoda, N. B., Feufel, J., Ubartaitė, G., Schneider, C. P., Rios, P. D. L., Hennig, J., Barducci, A., & Bukau, B. (2020) · Nature · doi:10.1038/s41586-020-2904-6 · Cited by 231
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Oliveira, L. M. A., Gasser, T., Edwards, R. H., Zweckstetter, M., Melki, R., Stefanis, L., Lashuel, H. A., Sulzer, D., Vekrellis, K., Halliday, G. M., et al. (2021) · npj Parkinson s Disease · doi:10.1038/s41531-021-00203-9 · Cited by 174
Metadata
- Authors
- Burmann, B. M., Gerez, J. A., Matečko-Burmann, I., Campioni, S., Kumari, P., Ghosh, D., Mazur, A., Aspholm, E. E., Šulskis, D., Wawrzyniuk, M., Bock, T., Schmidt, A., Rüdiger, S. G. D., Riek, R., & Hiller, S.
- Affiliations
- University of Basel (CH)
- ETH Zurich (CH)
- Wallenberg Centre for Molecular and Translational Medicine (SE)
- Utrecht University (NL)
- Corresponding author
- Burmann, Björn M.
- Riek, Roland
- Hiller, Sebastian
- ORCID
- Venue
- Nature
- Published
- 2019-12-04
- Volume
- 577
- Issue
- 7788
- Pages
- 127-132
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6930850
- OpenAlex
- W2992154881
- Cited by
- 255
- References
- 38
- Citations by year
- 2026: 12 · 2025: 32 · 2024: 38 · 2023: 56 · 2022: 53 · 2021: 36 · 2020: 27 · 2019: 1
- FWCI
- 20.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- edoc (University of Basel) (acceptedVersion, other-oa)
- PubMed Central (acceptedVersion)
- edoc (University of Basel) (acceptedVersion)
- DORA Empa (Swiss Federal Laboratories for Materials Science and Technology (Empa)) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Gothenburg University Publications Electronic Archive (Gothenburg University) (submittedVersion)
- edoc (University of Basel)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (166426, 148238, 164425, 128419)
- Vetenskapsrådet
- Göteborgs Universitet
- Wallenberg Centre for Molecular and Translational Medicine
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein, molecular chaperones, Parkinson's disease, protein aggregation, Hsc70, HSP90, HSP90β, Abelson kinase, mitochondrial localization, Lewy bodies, intrinsically disordered proteins, neurodegeneration
- MeSH terms
- Cell Survival, Humans, Magnetic Resonance Spectroscopy, Protein Processing, Post-Translational, Molecular Chaperones, alpha-Synuclein, HEK293 Cells
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