Author:
Bademosi Adekunle T.,Decet Marianna,Kuenen Sabine,Calatayud Carles,Swerts Jef,Gallego Sandra F,Schoovaerts Nils,Louros Nikolaos,Martin Ella,Karamanou Spyridoula,Sibarita Jean-Baptiste,Vints Katlijn,Gounko Natalia V.,Meunier Frédéric A.,Economou Anastassios,Versées Wim,Rousseau Frederic,Schymkowitz Joost,Soukup Sandra-F.,Verstreken Patrik
Abstract
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.
Publisher
Cold Spring Harbor Laboratory
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献