Impact of Insulin Signaling on Neurotoxicity in C. elegans Expressing TDP-43, an ALS Associated Protein
Location
SU-003
Department
Biology
Abstract
Amyotrophic Lateral Sclerosis (ALS) is an age-related neurodegenerative disease affecting motor neurons. A pathological feature shared among neurodegenerative diseases is protein aggregation. One such protein in ALS is 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 also suggests that these aggregates also influence sensory function. For example, olfactory dysfunction is a common bio marker for neurodegenerative diseases and ALS patients have been shown to have reduced ability to identify common odorants. Manipulation of signaling pathways that aid in the regulation of cellular stress responses may provide insight to addressing these motor and sensory pathologies. One such pathway is the insulin-like signaling (ILS) pathway. Mutations that reduce ILS signaling extend the life span of organisms and also increases 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. C. elegans share many conserved pathways with humans, making them excellent models for neurodegenerative diseases. These animals also have adept chemosensory systems capable of recognizing and discriminating against various chemical cues. Transgenic C. elegans expressing TDP-43 pan-neuronally exhibit reduced motor neuron functionality. Using behavioral thrashing assays, our lab sought to determine whether mutations in the insulin-like receptor, daf-2, would restore motor neuron function in TDP-43 expressing animals. Our preliminary data show C. elegans expressing both TDP-43 and the daf-2 mutation exhibit a significant increase in motor neuron activity. We now seek to determine how TDP-43 expression impacts chemosensation, an organism’s ability to interpret chemical stimuli from the environment. A chemosensory assay will be used to determine how TDP-43 influences detection of odorants. We expect that C. elegans expressing both TDP-43 and the daf-2 mutation 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 , Northeastern Illinois University
Impact of Insulin Signaling on Neurotoxicity in C. elegans Expressing TDP-43, an ALS Associated Protein
SU-003
Amyotrophic Lateral Sclerosis (ALS) is an age-related neurodegenerative disease affecting motor neurons. A pathological feature shared among neurodegenerative diseases is protein aggregation. One such protein in ALS is 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 also suggests that these aggregates also influence sensory function. For example, olfactory dysfunction is a common bio marker for neurodegenerative diseases and ALS patients have been shown to have reduced ability to identify common odorants. Manipulation of signaling pathways that aid in the regulation of cellular stress responses may provide insight to addressing these motor and sensory pathologies. One such pathway is the insulin-like signaling (ILS) pathway. Mutations that reduce ILS signaling extend the life span of organisms and also increases 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. C. elegans share many conserved pathways with humans, making them excellent models for neurodegenerative diseases. These animals also have adept chemosensory systems capable of recognizing and discriminating against various chemical cues. Transgenic C. elegans expressing TDP-43 pan-neuronally exhibit reduced motor neuron functionality. Using behavioral thrashing assays, our lab sought to determine whether mutations in the insulin-like receptor, daf-2, would restore motor neuron function in TDP-43 expressing animals. Our preliminary data show C. elegans expressing both TDP-43 and the daf-2 mutation exhibit a significant increase in motor neuron activity. We now seek to determine how TDP-43 expression impacts chemosensation, an organism’s ability to interpret chemical stimuli from the environment. A chemosensory assay will be used to determine how TDP-43 influences detection of odorants. We expect that C. elegans expressing both TDP-43 and the daf-2 mutation 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.