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