# Investigating the Role of MS4As in Amyotrophic Lateral Sclerosis

> **NIH NIH F31** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $36,080

## Abstract

Project Abstract (30 lines)
Neurodegenerative diseases (NDDs) are devastating conditions that rob individuals of their cognitive function,
mobility, and ability to function in the world. Ultimately, many of these diseases are fatal. Today, a combined
6.5 million Americans suffer from NDDs, encompassing Alzheimer’s disease (AD), Parkinson’s disease (PD),
multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). However, by
2030, 1 in 5 Americans will be over the age of 65, and because NDDs strike primarily in mid- to late-life, the
incidence is expected to soar as our population ages. These circumstances highlight the increasing urgency for
the development of effective treatments and cures for NDDs, which are currently lacking. While NDDs differ in
their inciting mechanisms, research has now clearly demonstrated the presence of shared features of
downstream pathophysiology, notably, the role of a dysregulated neuroinflammatory system. Recent studies in
humans and animal models have uncovered a population of microglia (Disease-associated microglia, DAMs),
that are defined by a distinct transcriptional signature, and are conserved across several different NDDs.
Intriguingly, the DAM signature includes upregulation of a number of different members of the MS4A gene
family, for which polymorphisms have been linked to AD by numerous genome-wide association studies
(GWAS). The upregulation of AD-associated MS4A genes in DAMs begs the questions of whether MS4A
genes might play a common role in NDDs, which share a DAM signature, and furthermore, whether MS4A
genes impact the functional properties of microglia in the context of NDDs. Excitingly, our lab has found that
across three animal NDD models (5XFAD, MAPT, SOD1G93A), mice deficient for either of two individual Ms4a
family members exhibit improved disease phenotypes, extension of lifespan, and amelioration of
histopathological disease hallmarks. Thus, this proposal will test the hypothesis that multiple MS4As act in
concert to drive pathology in a mouse model of ALS and regulate microglial transcriptional as well as functional
responses to the NDD milieu. To test this hypothesis, aim 1 will investigate the impact of simultaneous deletion
of the entire MS4A gene family on ALS. To this end, we have generated a novel mouse genetic reagent in
which the entire MS4A gene cluster is deleted. These mice will be crossed to the SOD1G93A ALS mouse model
and pathological features of ALS, including motor defects, lifespan, microgliosis, neuronal loss, and synapse
elimination will be assessed. Aim 2 will examine the impact of MS4A deficiency on the transcriptional and
functional properties of spinal cord microglia isolated from end-stage SOD1G93A mice. Specifically, I will utilize
single-cell RNA sequencing (scRNA-seq) in tandem with spatial transcriptomics (MERFISH) to evaluate the
impact of MS4A deletion on the DAM population. In parallel, I will examine how MS4A deficiency in vi...

## Key facts

- **NIH application ID:** 10995262
- **Project number:** 5F31NS134324-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Abigail Jean Hiller
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $36,080
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995262

## Citation

> US National Institutes of Health, RePORTER application 10995262, Investigating the Role of MS4As in Amyotrophic Lateral Sclerosis (5F31NS134324-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10995262. Licensed CC0.

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