TY - JOUR T1 - EndophilinA-dependent coupling between activity-dependent calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation JF - bioRxiv DO - 10.1101/2022.04.29.490010 SP - 2022.04.29.490010 AU - Adekunle T. Bademosi AU - Marianna Decet AU - Sabine Kuenen AU - Carles Calatayud AU - Jef Swerts AU - Sandra F Gallego AU - Nils Schoovaerts AU - Nikolaos Louros AU - Ella Martin AU - Spyridoula Karamanou AU - Jean-Baptiste Sibarita AU - Katlijn Vints AU - Natalia V. Gounko AU - Frédéric A. Meunier AU - Anastassios Economou AU - Wim Versées AU - Frederic Rousseau AU - Joost Schymkowitz AU - Sandra-F. Soukup AU - Patrik Verstreken Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/04/30/2022.04.29.490010.abstract N2 - Neuronal activity and neurotransmitter release cause use-dependent decline in protein function. However, it is unclear how this is coupled to local protein turnover and quality control mechanisms. Here we show that the endocytic protein Endophilin-A (EndoA/ENDOA1) couples activity-induced calcium influx to synaptic autophagy and neuronal survival. We identify single mutations in the EndoA flexible region that either increases EndoA diffusion and promotes autophagosome formation in the absence of calcium, or immobilizes EndoA and blocks autophagy, even in the presence of calcium. Hence, the EndoA flexible region is a switch that responds to calcium, regulating EndoA nanoscale synaptic organization and association with autophagosomes driving their formation. Interestingly, a pathogenic variant in the human ENDOA1 variable region that confers risk to Parkinson’s disease (PD), also confines ENDOA1 to the synaptic plasma membrane and equally blocks autophagy in flies in vivo and in induced human neurons. Thus, our work reveals a mechanism neurons use to connect neuronal activity to local protein turnover by autophagy, which is critical for neuronal survival.Competing Interest StatementThe authors have declared no competing interest. ER -