Presynaptic autophagy is coupled to the synaptic vesicle cycle via ATG-9

Abstract

Autophagy is a cellular degradation pathway essential for neuronal health and function. Autophagosome biogenesis occurs at synapses, is locally regulated, and increases in response to neuronal activity. The mechanisms that couple autophagosome biogenesis to synaptic activity remain unknown. In this study, we determine that trafficking of ATG-9, the only transmembrane protein in the core autophagy pathway, links thesynaptic vesicle cycle with autophagy. ATG-9-positive vesicles in C.elegans are generated from the trans-Golgi network via AP-3-dependent budding and delivered to presynaptic sites. At presynaptic sites, ATG-9 undergoes exo-endocytosis in an activity-dependent manner. Mutations that disrupt endocytosis, including a lesion in synaptojanin 1 associated with Parkinson's disease, result in abnormal ATG-9 accumulation at clathrin-rich synaptic foci and defects in activity-induced presynaptic autophagy. Our findings uncover regulated key steps of ATG-9 trafficking at presynaptic sites and provide evidence that ATG-9 exo-endocytosis couples autophagosome biogenesis at presynaptic sites with the activity-dependent synaptic vesicle cycle.