Impact of modulating cellular stress responses on organismal health in C. elegans expressing TDP-43

Location

Village Square

Department

Biology

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that severely impacts motor neuron function. Familial forms of ALS has been associated with mutations in the TARDBP gene, which encodes the Tar DNA binding protein 43 (TDP-43) that functions in RNA metabolism. Although TDP-43 functions primarily in the nucleus, over 90% of ALS patients have cytoplasmic aggregates of TDP-43 in their affected neurons. We are employing the nematode C. elegans to understand the relationship between TDP-43 toxicity and ALS. Given their short life cycle and prolific offspring generation, C. elegans makes a useful model organism to study human neurodegenerative diseases. Our laboratory has generated a transgenic line expressing TDP-43 pan-neuronally. Behavioral tests reveal motor neuron abnormalities in these animals, mimicking symptoms of ALS. In addition to impacting the worm's nervous system, TDP-43 expression leads to a decrease in fecundity, slower embryogenesis, and a delay in development compared to control worms. Enhancing the activity of cellular stress response pathways, such as the insulin signaling pathway (ILS), is a strategy to remedy disease associated symptoms. Therefore, we hypothesize that modifying the ILS system would mitigate TDP-43 toxicity. Using a genetic cross, a mutation in the insulin receptor was introduced into our transgenic lines. Currently, we are testing whether the receptor mutation restores fecundity for TDP-43 animals to wild-type levels. If so, this would suggest that modulating cellular stress response pathways protects organisms from TDP-43 toxicity.

Faculty Sponsor

Cindy Voisine, Northeastern Illinois University

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Apr 28th, 11:20 AM

Impact of modulating cellular stress responses on organismal health in C. elegans expressing TDP-43

Village Square

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that severely impacts motor neuron function. Familial forms of ALS has been associated with mutations in the TARDBP gene, which encodes the Tar DNA binding protein 43 (TDP-43) that functions in RNA metabolism. Although TDP-43 functions primarily in the nucleus, over 90% of ALS patients have cytoplasmic aggregates of TDP-43 in their affected neurons. We are employing the nematode C. elegans to understand the relationship between TDP-43 toxicity and ALS. Given their short life cycle and prolific offspring generation, C. elegans makes a useful model organism to study human neurodegenerative diseases. Our laboratory has generated a transgenic line expressing TDP-43 pan-neuronally. Behavioral tests reveal motor neuron abnormalities in these animals, mimicking symptoms of ALS. In addition to impacting the worm's nervous system, TDP-43 expression leads to a decrease in fecundity, slower embryogenesis, and a delay in development compared to control worms. Enhancing the activity of cellular stress response pathways, such as the insulin signaling pathway (ILS), is a strategy to remedy disease associated symptoms. Therefore, we hypothesize that modifying the ILS system would mitigate TDP-43 toxicity. Using a genetic cross, a mutation in the insulin receptor was introduced into our transgenic lines. Currently, we are testing whether the receptor mutation restores fecundity for TDP-43 animals to wild-type levels. If so, this would suggest that modulating cellular stress response pathways protects organisms from TDP-43 toxicity.