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

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 the synaptic 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. [Display omitted] • ATG-9 is localized in small vesicles in nerve terminals • ATG-9 vesicles undergo activity-dependent exo-endocytosis at presynaptic sites • Mutations in endocytic proteins disrupt ATG-9 localization at synapses • ATG-9 mislocalization is associated with defects in activity-induced synaptic autophagy Autophagosome biogenesis occurs near synapses and increases with neuronal activity. The mechanisms that couple synaptic autophagy with synaptic activity remain unknown. Yang et al. provide evidence that ATG-9 is on vesicles that undergo activity-dependent exo-endocytosis at synapses, thus coupling autophagosome biogenesis at presynaptic sites with the activity-dependent synaptic vesicle cycle. [ABSTRACT FROM AUTHOR]