Dataset Information

Forward Genetic Screen for Caenorhabditis elegans Mutants with a Shortened Locomotor Healthspan.

ABSTRACT: Two people with the same lifespan do not necessarily have the same healthspan. One person may retain locomotor and cognitive abilities until the end of life, while another person may lose them during adulthood. Unbiased searches for genes that are required to maintain locomotor ability during adulthood may uncover key regulators of locomotor healthspan. 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 ability. In one of the mutant strains, a nonsense mutation in elpc-2, which encodes Elongator Complex Protein Component 2, causes a progressive decline in locomotor ability during adulthood. Mutants and mutations identified in the present screen may provide insights into mechanisms of age-related locomotor impairment and the maintenance of locomotor healthspan.

SUBMITTER: Kawamura K

PROVIDER: S-EPMC6686916 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Forward Genetic Screen for <i>Caenorhabditis elegans</i> Mutants with a Shortened Locomotor Healthspan.

Kawamura Kazuto K Maruyama Ichiro N IN

G3 (Bethesda, Md.) 20190808 8

Two people with the same lifespan do not necessarily have the same healthspan. One person may retain locomotor and cognitive abilities until the end of life, while another person may lose them during adulthood. Unbiased searches for genes that are required to maintain locomotor ability during adulthood may uncover key regulators of locomotor healthspan. Here, we take advantage of the relatively short lifespan of the nematode <i>Caenorhabditis elegans</i> and develop a novel screening procedure t ...[more]

PMID: 31213517

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Project description:An abnormally expanded GGGGCC repeat in C9ORF72 is the most frequent causal mutation associated with amyotrophic lateral sclerosis (ALS)/frontotemporal lobar degeneration (FTLD). Both gain-of-function (gf) and loss-of-function (lf) mechanisms have been involved in C9ORF72 related ALS/FTLD. The gf mechanism of C9ORF72 has been studied in various animal models but not in C. elegans. In the present study, we described mutant C9ORF72 modeling in C. elegans and report the finding of two suppressor genes. We made transgenes containing 9 or 29 repeats of GGGGCC in C9ORF72, driven by either the hsp-16 promoters or the unc-119 promoter. Transgenic worms were made to carry such transgenes. Phenotypic analysis of those animals revealed that Phsp-16::(G4C2)29::GFP transgenic animals (EAB 135) displayed severe paralysis by the second day of adulthood, followed by lethality, which phenotypes were less severe in Phsp-16::(G4C2)9::GFP transgenic animals (EAB242), and absent in control strains expressing empty vectors. Suppressor genes of this locomotor phenotype were pursued by introducing mutations with ethyl methanesulfonate in EAB135, screening mutant strains that moved faster than EAB135 by a food-ring assay, identifying mutations by whole-genome sequencing and testing the underlying mechanism of the suppressor genes either by employing RNA interference studies or C. elegans genetics. Three mutant strains, EAB164, EAB165 and EAB167, were identified. Eight suppressor genes carrying nonsense/canonical splicing site mutations were confirmed, among which a nonsense mutation of F57A10.2/VAMP was found in all three mutant strains, and a nonsense mutation of acp-4/ACP2 was only found in EAB164. Knock down/out of those two genes in EAB135 animals by feeding RNAi/introducing a known acp-4 null allele phenocopied the suppression of the C9ORF72 variant related movement defect in the mutant strains. Translational conformation in a mammalian system is required, but our worm data suggest that altering acp-4/ACP2 encoding lysosomal acid phosphatase may provide a potential therapeutic method of reducing acp-4/ACP2 levels, as opposed or complementary to directly reducing C9ORF72, to relieve C9ORF72-ALS phenotypes. It also suggests that the C9ORF72-ALS/FTLD may share a pathophysiologic mechanism with vesicle-associated membrane protein-associated protein B, a homolog of F57A10.2/VAMP, which is a proven ALS8 gene.

Dataset Information

Forward Genetic Screen for Caenorhabditis elegans Mutants with a Shortened Locomotor Healthspan.

Publications

Forward Genetic Screen for <i>Caenorhabditis elegans</i> Mutants with a Shortened Locomotor Healthspan.

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