Bademosi, A.T., Decet, M., Kuenen, S., Calatayud, C., Swerts, J., Gallego, S.F., Schoovaerts, N., Karamanou, S., Louros, N., Martin, E., Sibarita, J.B., Vints, K., Gounko, N.V., Meunier, F.A., Economou, A., Versées, W., Rousseau, F., Schymkowitz, J., Soukup, S.F., Verstreken, P. (2023). EndophilinA-dependent coupling between activity-induced calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation.  Neuron 111(9): 1402--1422.e13.

FBrf0256464

Research paper

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.

PMC10166451 (PMC) (EuropePMC)