Forward genetic screen for Caenorhabditis elegans mutants with a shortened locomotor healthspan

Abstract

An inherited mutation is not always immediately toxic. Some mutations cause symptoms during youth, while other mutations cause symptoms during adulthood. Mutant animals that show delayed onset of disease symptoms may provide insights into mechanisms that maintain functional capacities during adulthood. Here, we take advantage of the relatively short lifespan of the nematode Caenorhabditis elegans and develop a novel screening procedure to collect mutants with locomotor deficits that become apparent in adulthood. After ethyl methanesulfonate mutagenesis, we isolated five C. elegans mutant strains that progressively lose adult locomotor activity. In one of the mutant strains, a nonsense mutation in Elongator Complex Protein Component 2 (elpc-2) causes a progressive decline in locomotor function. Other C. elegans elpc mutants were also unable to maintain locomotor function during adulthood, indicating that the Elongator complex plays a critical role in maintaining locomotor healthspan in C. elegans.\n\nSignificance StatementTwo people with the same lifespan do not necessarily have the same healthspan. One person may retain locomotor and cognitive functions until the end of life, while another person may lose them during adulthood. Currently, the network of genes that regulate healthspan is largely unknown. Unbiased searches for genes that work to maintain functional capacities during adulthood may uncover key regulators of healthspan. Here we isolated five Caenorhabditis elegans mutant strains that progressively lose their locomotor function in adulthood. Mutant analysis suggests that the Elongator complex regulates locomotor healthspan. Mutants and mutations identified in the present screen may provide insights into mechanisms of age-related locomotor impairment and may provide clues for improving healthspan.