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

• DOI: 10.1101/2022.04.29.490010
• Publication Date: 2022-05-02T18:25:18Z
• Authors: Adekunle T. Bademosi; Marianna Decet; Sabine Kuenen; Carles Calatayud; Jef Swerts; Sandra F Gallego; Nils Schoovaerts; Nikolaos Louros; Ella Martin; Spyridoula Karamanou; 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: 0301 basic medicine; 03 medical and health sciences

AbstractNeuronal 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.