Axon length-dependent synapse loss is mediated by neuronal cytokine-induced glial phagocytosis

Many neurodegenerative disorders (NDDs) preferentially affect neurons with long or complex axonal arbors, but our understanding of this specific vulnerability is limited. Using Drosophila larval class IV dendrite arborization (C4da) neurons, we found that neuronal activation of the integrated stress response (ISR) induces axon length-dependent degeneration (LDD). We identified the Interleukin-6 homologue unpaired 3 (upd3) as both necessary and sufficient for LDD in C4da neurons. Upd3 recruits glial cells to phagocytose presynapses preferentially on neurons with long axons, revealing an intrinsic axon length-dependent vulnerability to glia-mediated presynapse removal. Finally, we found that axon length-dependent presynapse loss in fly models of human NDDs utilized this pathway. Altogether, our studies identify inflammatory cytokine signaling from neurons to glia as a key determinant in axon length-dependent vulnerability.