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

• DOI: 10.1016/j.neuron.2023.02.001
• Publication Date: 2023-02-23T15:30:43Z
• Authors: Adekunle T. Bademosi; Marianna Decet; Sabine Kuenen; Carles Calatayud; Jef Swerts; Sandra F. Gallego; Nils Schoovaerts; Spyridoula Karamanou; Nikolaos Louros; Ella Martin; Jean-Baptiste Sib...; Katlijn Vints; Natalia V. Gounko; Frédéric A. Meunier; Anastassios Economou; Wim Versées; Frederic Rousseau; Joost Schymkowitz; Sandra-F. Soukup; Patrik Verstreken
• Keywords: Premovement neuronal activity; LRRK2

Neuronal activity causes use-dependent decline in protein function. However, it is unclear how this coupled to local quality control mechanisms. We show Drosophila that the endocytic Endophilin-A (EndoA) connects activity-induced calcium influx synaptic autophagy and neuronal survival a Parkinson disease-relevant fashion. Mutations disordered loop, including disease-risk mutation, render EndoA insensitive stimulation affect dynamics: when more flexible, its mobility membrane nanodomains increases, making available for autophagosome formation. Conversely, rigid, reduces, blocking stimulation-induced autophagy. Balanced required dopagminergic neuron survival, variant human ENDOA1 loop conferring risk disease also blocks nanodomain both vivo human-induced dopaminergic neurons. Thus, we reveal mechanism neurons use connect critical survival.