# Exploring The Brain Enriched E3 Ubiquitin Ligase TRIM9 in Alzheimer's Disease

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $427,625

## Abstract

PROJECT SUMMARY
Over the past ten years, my lab has focused on the function of the brain enriched E3 ubiquitin
ligase TRIM9. Our interest in TRIM9 originated from our identification of direct interactions
between TRIM9 and the actin polymerase VASP, the exocytic synaptic t-SNARE SNAP25 and
the netrin receptor DCC. This led us to hypothesize that TRIM9 coordinated cytoskeletal and
membrane remodeling during netrin triggered cellular shape change. Our work has shown that
TRIM9 regulates cytoskeletal dynamics and membrane remodeling during several critical stages
of morphogenesis of developing neurons and that deletion of Trim9 results in a complete loss of
spatial learning and memory. Several lines of evidence suggest that TRIM9 may continue to play
a critical role in the health and function of the aging neuron. First, TRIM9 enrichment in nervous
system continues into adult and is repressed in the brains of human patients with Parkinson’s
disease and dementia with Lewy bodies. Our work has shown that deletion of murine Trim9 results
in dramatic cognitive impairment, specifically in spatial learning and memory. Trim9-deficient mice
exhibit increased neuroinflammation, whereas increasing TRIM9 expression plays
neuroprotective roles following ischemic stroke. Finally, TRIM9 is a novel marker for
paraneoplastic cerebellar degeneration. Our recent proximity labeling experiments identified a
candidate TRIM9 interactome, which contained several proteins implicated in synaptic function
and Alzheimer’s disease. Preliminary data indicated TRIM9 affects dendritic spine density. Here,
we propose to expand our investigations into how TRIM9 specifically affects the shape and
function of the aging neuron, and susceptibility to AD.

## Key facts

- **NIH application ID:** 10467201
- **Project number:** 1R21AG077827-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Stephanie Gupton
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $427,625
- **Award type:** 1
- **Project period:** 2022-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467201

## Citation

> US National Institutes of Health, RePORTER application 10467201, Exploring The Brain Enriched E3 Ubiquitin Ligase TRIM9 in Alzheimer's Disease (1R21AG077827-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10467201. Licensed CC0.

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