Regulation of α-synuclein by chaperones in mammalian cells

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, Alexander Schmidt, Stefan G. D. Rüdiger, Roland Riek () and Sebastian Hiller ()
Additional contact information
Björn M. Burmann: University of Basel
Juan A. Gerez: Eidgenössische Technische Hochschule Zürich
Irena Matečko-Burmann: University of Basel
Silvia Campioni: Eidgenössische Technische Hochschule Zürich
Pratibha Kumari: Eidgenössische Technische Hochschule Zürich
Dhiman Ghosh: Eidgenössische Technische Hochschule Zürich
Adam Mazur: University of Basel
Emelie E. Aspholm: University of Gothenburg
Darius Šulskis: University of Gothenburg
Magdalena Wawrzyniuk: 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

Nature, 2020, vol. 577, issue 7788, 127-132

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-019-1808-9

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