Regulation of α-synuclein by chaperones in mammalian cells.

Abstract

Neurodegeneration in Parkinson’s disease is correlated with the occurrence of Lewy bodies, intracellular inclusions containing aggregates of the intrinsically disordered protein (IDP) α-Synuclein1. The aggregation propensity of α-Synuclein in cells is modulated by specific factors including posttranslational 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 vastly different molecular chaperones commonly recognize a canonical motif in α-Synuclein, consisting of the amino-terminus and a segment around Tyr39, hindering its aggregation. In-cell NMR experiments9 show the same transient interaction pattern preserved inside living mammalian cells. Specific inhibition of the interactions between α-Synuclein and the chaperones Hsc70 and Hsp90 yields transient membrane binding and triggers a remarkable re-localization of α-Synuclein to mitochondria and concomitant aggregate formation. Phosphorylation of α-Synuclein at Tyr39 directly impairs the chaperone interaction, thus providing a functional explanation for the role of Abelson kinase in Parkinson’s disease progression. Our results establish a master regulatory mechanism of α-Synuclein function and aggregation in mammalian cells, extending the functional repertoire of molecular chaperones and opening new perspectives for therapeutic interventions for Parkinson’s disease.