IMPACT OF INSULIN SIGNALING ON NEUROTOXICITY IN C. ELEGANS EXPRESSING TDP-43, AN ALS ASSOCIATED PROTEIN
Location
SU-217
Department
Biology
Abstract
Amyotrophic Lateral Sclerosis (ALS) is an age-related neurodegenerative disease affecting motor neurons. A pathological feature shared among neurodegenerative diseases is the aggregation of proteins such as the ALS associated Tar DNA-binding protein 43 (TDP-43). Proteotoxic stress induced by TDP-43 aggregates leads to inappropriate signaling at the neuromuscular junction. This causes muscular atrophy and the progressive loss of voluntary muscle movement. Growing evidence suggests that these aggregates also influence sensory function. For example, many ALS patients have reduced ability to identify common odorants. Manipulation of signaling pathways that regulate cellular stress responses may offer therapeutic interventions for these motor and sensory pathologies. Mutations that reduce insulin-like signaling (ILS) are known to increase cellular stress resistance. We are using the nematode Caenorhabditis elegans to determine the impact of the ILS pathway on ameliorating the neurotoxicity of TDP-43. Using well-characterized behavioral assays, we have shown that transgenic C. elegans expressing TDP-43 pan-neuronally exhibit reduced motor and chemosensory neuron functionality. Our lab sought to determine whether mutations in the insulin-like receptor, daf-2, would restore neuron function in TDP-43 expressing animals. Our data show C. elegans expressing TDP-43 in the daf-2 mutant background exhibit a significant increase in motor neuron activity. We are currently exploring whether the daf-2 mutation also restores the ability to detect volatile odorants. We hypothesize that C. elegans expressing TDP-43 in the daf-2 mutant background will exhibit recovery of chemosensation. Understanding ways to address proteotoxicity and improve neuronal functionality may assist in improving the prognosis of individuals afflicted with ALS.
Faculty Sponsor
Cindy Voisine
IMPACT OF INSULIN SIGNALING ON NEUROTOXICITY IN C. ELEGANS EXPRESSING TDP-43, AN ALS ASSOCIATED PROTEIN
SU-217
Amyotrophic Lateral Sclerosis (ALS) is an age-related neurodegenerative disease affecting motor neurons. A pathological feature shared among neurodegenerative diseases is the aggregation of proteins such as the ALS associated Tar DNA-binding protein 43 (TDP-43). Proteotoxic stress induced by TDP-43 aggregates leads to inappropriate signaling at the neuromuscular junction. This causes muscular atrophy and the progressive loss of voluntary muscle movement. Growing evidence suggests that these aggregates also influence sensory function. For example, many ALS patients have reduced ability to identify common odorants. Manipulation of signaling pathways that regulate cellular stress responses may offer therapeutic interventions for these motor and sensory pathologies. Mutations that reduce insulin-like signaling (ILS) are known to increase cellular stress resistance. We are using the nematode Caenorhabditis elegans to determine the impact of the ILS pathway on ameliorating the neurotoxicity of TDP-43. Using well-characterized behavioral assays, we have shown that transgenic C. elegans expressing TDP-43 pan-neuronally exhibit reduced motor and chemosensory neuron functionality. Our lab sought to determine whether mutations in the insulin-like receptor, daf-2, would restore neuron function in TDP-43 expressing animals. Our data show C. elegans expressing TDP-43 in the daf-2 mutant background exhibit a significant increase in motor neuron activity. We are currently exploring whether the daf-2 mutation also restores the ability to detect volatile odorants. We hypothesize that C. elegans expressing TDP-43 in the daf-2 mutant background will exhibit recovery of chemosensation. Understanding ways to address proteotoxicity and improve neuronal functionality may assist in improving the prognosis of individuals afflicted with ALS.