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Regulation of α-synuclein by chaperones in mammalian cells

Burmann, Björn M. and Gerez, Juan A. and Matečko-Burmann, Irena and Campioni, Silvia and Kumari, Pratibha and Ghosh, Dhiman and Mazur, Adam and Aspholm, Emelie E. and Šulskis, Darius and Wawrzyniuk, Magdalena and Bock, Thomas and Schmidt, Alexander and Rüdiger, Stefan G. D. and Riek, Roland and Hiller, Sebastian. (2020) Regulation of α-synuclein by chaperones in mammalian cells. Nature, 577. pp. 127-132.

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Official URL: https://edoc.unibas.ch/74983/

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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-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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Hiller)
05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Research IT (Podvinec)
UniBasel Contributors:Hiller Odermatt, Sebastian and Podvinec, Michael
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Research
ISSN:0028-0836
e-ISSN:1476-4687
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:24 Apr 2020 03:10
Deposited On:10 Feb 2020 16:40

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