# Molecularly Dissecting How Obesity-Promoting Diets Activate the Neuronal Protein Aggregation Factor MOAG-4/SERF2

> **NIH NIH R21** · UNIVERSITY OF VIRGINIA · 2024 · $218,261

## Abstract

Abstract
Obesity is an independent risk factor for Alzheimer's disease (AD). With obesity prevalence at 37% and rising,
the urgency to uncouple obesity from AD is pressing. Understanding the molecular connection between obesity
and AD is crucial to disrupt this link.
The Principal Investigator (PI) has reported accelerated neurolocomotor decline in a C. elegans model of diet-
induced obesity (DIO)—the most common form of obesity in humans. Moreover, the PI has pioneered single-cell
RNA sequencing (scRNAseq) in adult C. elegans, utilizing it to delineate the transcriptomes of lean and obese
worms with single-cell precision. These studies have shown that DIO prompts a greater than 30-fold induction of
a gene named Modulator of AGgregation 4 (moag-4). It has been established that elevated levels of the MOAG-4
protein induce early-onset protein aggregation and other cellular AD-like phenotypes in C. elegans, mice, and
human cultured cells. This increase is causatively associated with behavioral and cognitive declines in both
worms and mice. Based on the present evidence, the PI hypothesizes that moag-4 is a causal link between
obesity and AD. Supporting this hypothesis, RNAi-mediated suppression of moag-4 attenuates the
neurolocomotor decline typically observed in obese C. elegans.
During the two-year tenure of this exploratory award, the PI aims to: 1) Genetically identify the molecular
pathway/s through which obesity activates moag-4 in C. elegans neurons, and 2) Identify the specific aspects of
obesity-induced neurological and motor decline that are mediated by moag-4.
Following this R21 phase, the research would expand to include mouse models to ascertain if the pathways
identified in worms are conserved in mammals. The overarching objective is to delineate the moag-4/SERF2
pathway that connects obesity to AD with sufficient precision to therapeutically target it, ultimately mitigating
the impact of AD on individuals, caregivers, and the wider society.

## Key facts

- **NIH application ID:** 10985373
- **Project number:** 1R21AG085597-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Eyleen Jorgelina O'Rourke
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $218,261
- **Award type:** 1
- **Project period:** 2024-07-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985373

## Citation

> US National Institutes of Health, RePORTER application 10985373, Molecularly Dissecting How Obesity-Promoting Diets Activate the Neuronal Protein Aggregation Factor MOAG-4/SERF2 (1R21AG085597-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10985373. Licensed CC0.

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