Regulation of α-synuclein by chaperones in mammalian cells

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. Chaperones interact with a canonical motif in α-synuclein, which can be prevented by phosphorylation of α-synuclein at Tyr39, whereas inhibition of this interaction leads to the localization of α-synuclein to the mitochondria and aggregate formation.