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

Authors

Naden Khateb, Miri Shwartsburd, Eden Grig, Shelly Vogelesang-Ganon, Tsneem Fauzi, Malak Ayoub, Ketty Hakim-Mishnaevski, Estee Kurant

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 40. Pages e2622558123. Oct 06, 2026. Epub Sep 28, 2026.

Abstract

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.

PMID:
42804623
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.

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