Title: Nonsense-mediated mRNA in Age-related Mobility Decline
Mobility decline is a hallmark of aging that negatively affects the quality of life. The integrity of the neurons and muscles forming the motor system is vital for successful mobility during aging. RNA homeostasis declines in various tissues during aging, including the neurons and muscle, suggesting a potential role in age-related mobility decline. The nonsense-mediated mRNA decay (NMD) pathway is a conserved RNA surveillance system that could be decreased with age. However, the role of NMD in age-related mobility decline remains obscure. My long-term goal is to investigate how aging affects the expression and quality of mRNA in the motor system, thereby leading to mobility decline. The objective of this project is to use the nematode Caenorhabditis elegans (C. elegans) to investigate the age-related changes in the NMD pathway in motor neurons and muscle as a mechanism behind age-related mobility decline. Understanding the relationship between the NMD pathway and neuromuscular system during aging will provide fundamental knowledge that holds the potential for RNA homeostasis as a target to improve mobility.
The first aim of the project is to investigate the relationship between NMD activity and age-related mobility decline in the neuromuscular system. An automated worm behavior tracker will be used to determine the correlation between body mobility and NMD activity across the lifespan. In parallel, the morphology of motor neurons, muscles, and their synapses will be assessed using fluorescent microscopy. Both wild-type worms and mutants defective in NMD activity will be used. The second aim is to investigate the effects of modulating NMD activity on mobility and the integrity of the neuromuscular system during aging. Genetic overexpression of key NMD components will be used as well as artificial modulation by using small molecules previously identified as potential effectors of NMD. Ideally, the proposed study could expedite translational research because previous mammalian studies suggest the NMD pathway as a potential therapeutic target for neurological and muscular disorders. Given that NMD is evolutionarily conserved, understanding how NMD works in a spatial-temporal manner to regulate the motor system during aging could support its therapeutic potential.
Dr. McElroy is now starting her T32 fellowship under the mentorship of Dr. Sung Min Han. She is eager to explore how NMD affects mobility in the context of aging.