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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).”
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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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