# Investigating the role of myenteric macrophages in enteric synucleinopathy

> **NIH NIH F30** · UNIVERSITY OF FLORIDA · 2023 · $41,913

## Abstract

Project Summary/Abstract: Enteric synucleinopathy is characterized by the deposition of misfolded α-
synuclein aggregates in enteric neurons and induces long-term gastrointestinal dysfunction. Enteric
synucleinopathy is also thought to be a precursor to CNS synucleinopathies, such as Parkinson’s’ Disease (PD),
PD-Dementia, and Lewy Body Dementia, a collective group of debilitating neurodegenerative disorders that
cause motor, cognitive, and autonomic dysfunction. Notably, even after development of CNS synucleinopathy
gastrointestinal symptoms remain as major causes of morbidity in these patients. However, a poor understanding
of the cellular processes underlying development and progression has precluded any therapies aimed at
preventing synucleinopathy progression into the brain or mitigating GI dysfunction. In the central nervous system
resident macrophages, the microglia, can have pronounced impact on synucleinopathy. Enteric neuron-
associated macrophages resemble microglia at rest in that they support nearby neurons. But unlike microglia,
their phenotype and role in enteric synucleinopathy is undefined. Therefore, the Aims of this proposal seek to
define how enteric neuron associated macrophages promote or palliate the neuropathological and
neurophysiological aspects of enteric synucleinopathy.
Aim 1: Explicate the macrophage subpopulations that influence spread of phosphorylated α-synuclein
pathology in a mouse model of enteric synucleinopathy. Herein, I will characterize macrophage involvement
in the development and spread of enteric, phosphorylated α-synuclein neuropathology and define the immune
transcriptional landscape associated with this state. My working hypothesis for this aim is that a sub-population
of macrophages initially take up α-synuclein to mitigate pathology and adopt an antigen-presentation phenotype
to activate T-cells
Aim 2: Determine how myenteric macrophages modulate enteric neuronal network functional and
structural connectivity in a mouse model of enteric synucleinopathy. Alterations in myenteric macrophage
phenotype and α-synuclein pathology have been shown to induce enteric neuronal network dysfunction and gut
dysmotility independently, but how they work in concert in the setting of enteric synucleinopathy remains
unknown. More specifically, whether myenteric macrophages mediate α-synuclein’s effects on network
connectivity and network output has not been investigated. Thus, my working hypothesis for this aim is that α-
synuclein pathology will prompt myenteric macrophages to engage in excessive, complement-dependent
synaptic pruning leading to disrupted enteric neuronal network activity. Together, these experiments will reveal
how neuro-immune interactions influence the early stages of synucleinopathies.

## Key facts

- **NIH application ID:** 10678094
- **Project number:** 1F30NS129283-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Phillip Mackie
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $41,913
- **Award type:** 1
- **Project period:** 2023-05-16 → 2026-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10678094

## Citation

> US National Institutes of Health, RePORTER application 10678094, Investigating the role of myenteric macrophages in enteric synucleinopathy (1F30NS129283-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10678094. Licensed CC0.

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