Masking phosphatidylserine prevents neuronal loss in two distinct Drosophila models of neurodegeneration

Neuronal loss is a hallmark of neurodegenerative diseases. Phosphatidylserine (PS), a key “eat me” signal, is exposed on stressed viable neurons, triggering their premature phagocytosis by activated glia. We investigated whether PS masking could serve as a universal strategy to prevent neuronal loss in two distinct Drosophila models of neurodegeneration: an adult-stage-specific knockdown of skpA and a Huntington’s disease model initiated during embryogenesis. Both models exhibit neuronal loss, motor dysfunction, and reduced lifespan. To mask PS, we used a truncated form of Milk Fat Globule-Epidermal Growth Factor 8, a glycoprotein that binds PS without promoting engulfment. PS masking preserved two neuronal populations in both models, indicating that these neurons were eliminated alive via phagoptosis. Motor function and lifespan were improved to varying degrees, depending on the timing and severity of neuronal damage. These findings reveal that aberrant glial phagocytosis contributes to neuronal vulnerability and identify PS masking as a promising therapeutic approach for neurodegenerative diseases.