Author
Listed:
- Björn M. Burmann
(University of Basel
University of Gothenburg
University of Gothenburg)
- Juan A. Gerez
(Eidgenössische Technische Hochschule Zürich)
- Irena Matečko-Burmann
(University of Basel
University of Gothenburg
University of Gothenburg)
- Silvia Campioni
(Eidgenössische Technische Hochschule Zürich
Empa)
- Pratibha Kumari
(Eidgenössische Technische Hochschule Zürich)
- Dhiman Ghosh
(Eidgenössische Technische Hochschule Zürich)
- Adam Mazur
(University of Basel)
- Emelie E. Aspholm
(University of Gothenburg
University of Gothenburg)
- Darius Šulskis
(University of Gothenburg
University of Gothenburg)
- Magdalena Wawrzyniuk
(Utrecht University
Utrecht University)
- Thomas Bock
(University of Basel)
- Alexander Schmidt
(University of Basel)
- Stefan G. D. Rüdiger
(Utrecht University)
- Roland Riek
(Eidgenössische Technische Hochschule Zürich)
- Sebastian Hiller
(University of Basel)
Abstract
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-synuclein1. The aggregation propensity of α-synuclein in cells is modulated by specific factors that include post-translational modifications2,3, Abelson-kinase-mediated phosphorylation4,5 and interactions with intracellular machineries such as molecular chaperones, although the underlying mechanisms are unclear6–8. 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 experiments9 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.
Suggested Citation
Björn M. Burmann & Juan A. Gerez & Irena Matečko-Burmann & Silvia Campioni & Pratibha Kumari & Dhiman Ghosh & Adam Mazur & Emelie E. Aspholm & Darius Šulskis & Magdalena Wawrzyniuk & Thomas Bock & Ale, 2020.
"Regulation of α-synuclein by chaperones in mammalian cells,"
Nature, Nature, vol. 577(7788), pages 127-132, January.
Handle:
RePEc:nat:nature:v:577:y:2020:i:7788:d:10.1038_s41586-019-1808-9
DOI: 10.1038/s41586-019-1808-9
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Citations
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Cited by:
- Jemil Ahmed & Tessa C. Fitch & Courtney M. Donnelly & Johnson A. Joseph & Tyler D. Ball & Mikaela M. Bassil & Ahyun Son & Chen Zhang & Aurélie Ledreux & Scott Horowitz & Yan Qin & Daniel Paredes & Sun, 2022.
"Foldamers reveal and validate therapeutic targets associated with toxic α-synuclein self-assembly,"
Nature Communications, Nature, vol. 13(1), pages 1-17, December.
- Sabine M. Ulamec & Roberto Maya-Martinez & Emily J. Byrd & Katherine M. Dewison & Yong Xu & Leon F. Willis & Frank Sobott & George R. Heath & Patricija Oosten Hawle & Vladimir L. Buchman & Sheena E. R, 2022.
"Single residue modulators of amyloid formation in the N-terminal P1-region of α-synuclein,"
Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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