Inflammatory cytokine upd3 induces axon length-dependent synapse removal by glia.

Abstract

Many neurodegenerative disorders (NDDs) preferentially affect neurons with long or complex axonal arbors but the cellular and molecular bases for neurite length-dependent vulnerability of neurons to degeneration is largely unknown. Using <i>Drosophila</i> sensory neurons as a model system we show that neuronal activation of the integrated stress response triggers expression of the Interleukin-6 homolog <i>unpaired 3</i> (<i>upd3</i>), which is both necessary and sufficient for axon length-dependent degeneration of presynapses. Upd3 activates phagocytic glia, triggering phagocytic removal of presynapses preferentially on neurons with long axons, thus revealing an intrinsic axon length-dependent vulnerability to glial insult. Finally, we found that axon length-dependent presynapse loss in fly models of human NDDs utilized this pathway, requiring <i>upd3</i> and glial expression of the phagocytic receptor draper. Our studies identify inflammatory cytokine signaling and glial phagocytosis as key determinants of axon length-dependent vulnerability, thus mechanistically linking these hallmarks of NDDs.