# The role of gasdermins in microglial activation and neurodegeneration in ALS/FTD

> **NIH NIH F32** · HARVARD MEDICAL SCHOOL · 2024 · $74,284

## Abstract

7. Project Summary/Abstract
 The goal of this proposal is to elucidate a role for microglial gasdermin-D in the severity of
neurodegeneration in models of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Despite widespread evidence for microglial activation in several neurodegenerative diseases, the precise
mechanisms governing these microglial responses are not well understood. Gasdermin-D (GSDMD) is a pore-
forming protein expressed in peripheral macrophages that initiates a proinflammatory form of cell death termed
pyroptosis. I have evidence that microglia highly express GSDMD in the central nervous system, and that in vitro
primary microglia similarly form GSDMD pores when exposed to inflammasome triggers. Using the well-
described SOD1G93A model of ALS, I found a significant increase in microglial Gsdmd transcription and activation
at the protein level in the spinal cord as paralysis progresses. In a separate model of C9ORF72-associated FTD,
I found Gsdmd expression increases in the brain after neuronal overexpression of a dipeptide repeat expansion
(DRE) protein. While Gsdmd expression is similarly increased in both models, using a Gsdmd null animal in
either disease context results in an opposite effect on animal survival where GSDMD drives protection in the
ALS disease model but disease progression in the C9ORF72 model of FTD. Transcriptomic work on microglia
across development and in neurodegeneration suggests microglia have differing immune functions based on
their resident location in the brain, animal age, and in health versus disease. I aim to further understand the
heterogeneity of microglial responses in the CNS in neurodegeneration by addressing the following questions:
1) How does Gsdmd expression drive protection in the SOD1G93A model of ALS (Aim 1) but conversely drive
disease progression in a model of C9ORF72 FTD (Aim 2)? 2) How do microglial transcriptional profiles change
with loss of Gsdmd expression in the spinal cord and brain in ALS and FTD disease models (Aims 1 and 2)? I
hypothesize microglial GSDMD results in opposing effects on survival outcome due to disease context-
dependent changes in microglial immune profiles. To test this hypothesis, I plan to use flow cytometry and single
cell RNAseq which are powerful approaches to interrogating microglial function and techniques for which I will
acquire new scientific skills. I also have developed strong collaborations to model FTD with AAV strategies, as
well as a strong mentoring team including my mentor Dr. Isaac Chiu as well as Dr. Judy Lieberman, Dr. Beth
Stevens, and Dr. Leonard Petrucelli who are experts in neuroimmunology, gasdermin biology, microglia, and
neurodegeneration, respectively. Together, I am in a strong position to interrogate microglial Gsdmd activation
in ALS and FTD neurodegeneration. In the process of completing the experiments in this proposal, I will receive
training in a variety of immunology and neurobiology approaches that...

## Key facts

- **NIH application ID:** 11032726
- **Project number:** 5F32AG084174-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Georgia Gunner
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,284
- **Award type:** 5
- **Project period:** 2023-09-30 → 2026-03-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11032726

## Citation

> US National Institutes of Health, RePORTER application 11032726, The role of gasdermins in microglial activation and neurodegeneration in ALS/FTD (5F32AG084174-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11032726. Licensed CC0.

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