EndophilinA-dependent coupling between activity-induced calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation

Neuronal activity causes use-dependent decline in protein function. However, it is unclear how this is coupled to local quality control mechanisms. We show in Drosophila that the endocytic protein Endophilin-A (EndoA) connects activity-induced calcium influx to synaptic autophagy and neuronal survival in a Parkinson disease-relevant fashion. Mutations in the disordered loop, including a Parkinson disease-risk mutation, render EndoA insensitive to neuronal stimulation and affect protein dynamics: when EndoA is more flexible, its mobility in membrane nanodomains increases, making it available for autophagosome formation. Conversely, when EndoA is more rigid, its mobility reduces, blocking stimulation-induced autophagy. Balanced stimulation-induced autophagy is required for dopagminergic neuron survival, and a variant in the human ENDOA1 disordered loop conferring risk to Parkinson disease also blocks nanodomain protein mobility and autophagy both in vivo and in human-induced dopaminergic neurons. Thus, we reveal a mechanism that neurons use to connect neuronal activity to local autophagy and that is critical for neuronal survival. •Pre-synaptic Ca2+ influx induces autophagy at Drosophila synapses•Ca2+ influx drives changes in EndoA rigidity, localization, and synaptic autophagy•Starvation and Ca2+ influx independently trigger autophagosome formation•A Parkinson disease-linked mutation in EndoA1 blocks synaptic autophagy Bademosi, Decet, and Kuenen et al. show that synaptic autophagy is triggered by calcium influx during neuronal activity. This is mediated by rigidity changes in EndoA structure driving protein mobility and protein re-localization. A Parkinson disease-linked variant in EndoA1 impinges on this process and blocks autophagy in flies and human neurons.