This research proposal investigates how a chemical modification called N6-methyladenosine (m6A) on messenger RNA influences brain health, specifically focusing on its role in sleep regulation, learning and memory, and neurodegenerative diseases such as Alzheimer’s. m6A is an RNA modification that affects gene expression and protein production, and it has been linked to brain development, cognitive aging, and neurological disorders. Recent findings suggest m6A regulates the circadian clock, which controls sleep patterns critical for maintaining brain health. Preliminary data from our lab indicate that removing Mettl3, the enzyme responsible for adding m6A, results in fragmented sleep, impaired learning and memory, protein aggregation in the brain, and shorter lifespan in fruit flies (Drosophila), all of which mirror symptoms commonly observed in neurodegenerative conditions. Using Drosophila as a model organism due to its genetic tractability, short lifespan, and evolutionary conservation of m6A mechanisms, we aim to identify specific neuronal circuits where m6A acts to regulate these neurological processes. We will investigate whether deficits in sleep, learning, memory, and protein aggregation are independently regulated or interconnected through common pathways. Additionally, we will examine how m6A levels change with aging by measuring m6A at multiple time points throughout the lifespan and explore whether manipulating these levels can delay cognitive decline and extend lifespan. Finally, we will test if targeted genetic or pharmacological modulation of m6A can alleviate symptoms in fly models of Alzheimer’s disease. By clarifying the role of m6A in these processes, our research could lead to novel therapeutic approaches targeting m6A pathways to improve cognitive function and slow neurodegeneration. Understanding these molecular mechanisms connecting m6A with sleep regulation and cognitive function may ultimately inform strategies to treat age-related cognitive decline and neurodegenerative diseases in humans.
