# Mechanisms of natural phosphatidylserine exposure in the nervous system

> **NIH NIH R21** · CORNELL UNIVERSITY · 2022 · $235,520

## Abstract

PROJECT SUMMARY/ABSTRACT
A functional nervous system requires active maintenance of neuronal structures by supporting cells. Some
supporting cells are phagocytes that engulf unnecessary or damaged neuronal parts by detecting “eat-me”
signals exposed on neuronal membranes. Phosphatidylserine (PS) has been shown to be a potent neuronal
eat-me signal that mediates phagocytosis of neurons in many neurodegenerative events. Normally hidden in
the inner leaflet of the plasma membrane, this phospholipid is exposed specifically on the degenerative parts of
neurons to induce phagocytosis. However, it is unknown whether heathy neurons expose PS on their surface
in ways unrelated to phagocytosis in vivo. Using an in vivo system to visualize PS exposure on peripheral
sensory neurons, it was discovered that certain neurons in Drosophila naturally expose PS on their dendrites in
spatially defined patterns without inducing phagocytosis. This finding raises two specific and important
questions: (1) How is PS exposure spatially maintained on these dendrites? (2) What prevents these PS-
exposing dendrites from being engulfed by phagocytes? The overall objectives of this proposal are to
investigate the mechanistic causes of this unexpected PS exposure on healthy neurons and to elucidate how
these PS-exposing neurons are protected against phagocytosis-induced degeneration. Answering these
questions is an important step toward our long-term goal of elucidating neuron-phagocyte interactions in the
development, maintenance, and degeneration of the nervous system. To achieve these objectives, the
following two aims are proposed: (1) Elucidate the mechanisms underlying natural PS exposure on dendrites.
Specifically, the endogenous PS flippase ATP8A will be fluorescently tagged in specific neurons to investigate
whether the flippase distribution along dendrites defines the patterns of natural PS exposure. In addition, the
roles of dendrite excitation and membrane potential in natural PS exposure will be examined. (2) Define the
pathways that regulate susceptibility of dendrites to PS-induced degeneration. A pilot RNAi screen revealed
the involvement of a septate junction component and a Deg/ENaC sodium channel in regulating the resistance
of PS-exposing dendrites to phagocytosis. Thus, it will be tested whether septate junction proteins protect PS-
exposing dendrites from being engulfed and whether neuronal activity promotes PS-related degeneration.
Together, these aims will define the molecular basis of natural neuronal PS exposure and reveal new
mechanisms of neuroprotection. The knowledge gained in this project will be important for understanding how
different neuronal types utilize the same phagocytic signal to interact with phagocytes in diverse ways.

## Key facts

- **NIH application ID:** 10428834
- **Project number:** 1R21NS127052-01
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Chun Han
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $235,520
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428834

## Citation

> US National Institutes of Health, RePORTER application 10428834, Mechanisms of natural phosphatidylserine exposure in the nervous system (1R21NS127052-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10428834. Licensed CC0.

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