Inflammatory cytokine upd3 induces axon length–dependent synapse removal by glia

• DOI: 10.1073/pnas.2422752122
• Publication Date: 2025-05-20T17:40:02Z
• Authors: Federico Marcello...; Chang Yin; Jessica M. Huang; Neena Dhiman; Peter Soba; Jay Z. Parrish
• Keywords: Neurite

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 to degeneration is largely unknown. Using Drosophila sensory as a model system we show that neuronal activation integrated stress response triggers expression Interleukin-6 homolog unpaired 3 ( upd3 ), which both necessary sufficient axon length–dependent presynapses. Upd3 activates phagocytic glia, triggering removal presynapses on axons, thus revealing an intrinsic glial insult. Finally, found presynapse loss in fly models human NDDs utilized this pathway, requiring receptor draper. Our studies identify inflammatory cytokine signaling phagocytosis key determinants vulnerability, mechanistically linking these hallmarks NDDs.