Regulation of α-synuclein by chaperones in mammalian cells.

Burmann BM, Gerez JA, Matečko-Burmann I, Campioni S, Kumari P, Ghosh D, Mazur A, Aspholm EE, Šulskis D, Wawrzyniuk M, Bock T, Schmidt A, Rüdiger SGD, Riek R, Hiller S

Nature 577 (7788) 127-132 [2020-01-00; online 2019-12-04]

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 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.

Swedish NMR Centre (SNC) [Service]

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PubMed 31802003

DOI 10.1038/s41586-019-1808-9

Crossref 10.1038/s41586-019-1808-9

pii: 10.1038/s41586-019-1808-9
pmc: PMC6930850
mid: EMS84680