Regulation of ?-synuclein by chaperones in mammalian cells.

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 ?-synuclein1. The aggregation propensity of ?-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 ?-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 ?-synuclein, consisting of the N terminus and a segment around Tyr39, and hinder the aggregation of ?-synuclein. NMR experiments9 in cells show that the same transient interaction pattern is preserved inside living mammalian cells. Specific inhibition of the interactions between ?-synuclein and the chaperone HSC70 and members of the HSP90 family, including HSP90?, results in transient membrane binding and triggers a remarkable re-localization of ?-synuclein to the mitochondria and concomitant formation of aggregates. Phosphorylation of ?-synuclein at Tyr39 directly impairs the interaction of ?-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 ?-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.

SUBMITTER: Burmann BM 

PROVIDER: S-EPMC6930850 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature