Phagocytosis-driven neurodegeneration through opposing roles of an ABC transporter in neurons and phagocytes

Lipid homeostasis is critical to neuronal survival. ATP-binding cassette A (ABCA) proteins are lipid transporters associated with neurodegenerative diseases. How ABCA transporters regulate lipid homeostasis in neurodegeneration is an outstanding question. Here we report that the <i>Drosophila</i> ABCA protein engulfment ABC transporter in the ovary (Eato) regulates phagocytosis-dependent neurodegeneration by playing opposing roles in neurons and phagocytes: In neurons, Eato prevents dendrites and axons from being attacked by neighboring phagocytes; in phagocytes, Eato sensitizes the cell for detecting neurons as engulfment targets. Thus, <i>Eato</i> deficiency in neurons alone causes phagocytosis-dependent neurite degeneration, but additional <i>Eato</i> loss from phagocytes suppresses the neurite degeneration. Mechanistically, Eato functions by removing the eat-me signal phosphatidylserine from the cell surface in both neurons and phagocytes. Multiple human and worm ABCA homologs can rescue <i>Eato</i> loss in phagocytes but not in neurons, suggesting both conserved and cell type-specific activities of ABCA proteins. These results imply possible mechanisms of neuron-phagocyte interactions in neurodegenerative diseases.