figueroa, zelene et al. (2015) International Worm Meeting "C. elegans Model of Amyotrophic Lateral Sclerosis: Understanding the Role of TDP-43 Expression on HSN Motor Neuron Function."

[

International Worm Meeting,

2015]

Neurodegenerative diseases are often characterized by a continual loss of neuron abilities. Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease is a progressive neurodegenerative disease affecting nerve cells that are important for locomotion. When motor neurons atrophy, due to their lack of regenerative ability, muscle control is severely impaired. Some individuals with ALS carry mutations in a gene called TDP-43. It is hypothesized that mutations in TDP-43 cause TDP-43 to aggregate leading to motor neuron degeneration. We have generated a nematode C. elegans model for ALS. This model was made by cloning the human version of the TDP-43 gene under the control of a pan-neuronal promoter. Taking advantage of the transparency of C. elegans, the human TDP-43 was tagged with a YFP (yellow fluorescent protein) to provide visual representation of its aggregation during development and aging. Egg laying assays were performed as an indication of neuronal function, specifically, to monitor TDP-43 and the effect of its aggregation on HSN motor neurons, which are responsible for vulval muscle contraction and thus the reproductive success of C. elegans. Preliminary data suggests that there is a 60% decrease in progeny production in animals expressing TDP-43. Furthermore, TDP-43 expressing animals have a 40% decrease in egg laying rate compared to wild-type animals. Taken together, our data indicates defects in HSN motor neurons. Our studies using this C. elegans model will continue to enhance our understanding of the connection between the proposed aggregation of TDP-43 and motor neuronal defects associated with ALS, through the examination of HSN motor neuron defects demonstrated in the TDP-43 transgenic C. elegans lines. .

Nguyen, Quan et al. (2015) International Worm Meeting "Proteostasis imbalances impact sensory and motor neuron function in C. elegans animals expressing TDP-43."

Voisine, Cindy, Figueroa, Zelene, Nguyen, Quan, Rendleman, Emily

[

International Worm Meeting,

2015]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons. While the vast majority of ALS cases occur sporadically, about 5-10% of ALS cases are inherited. ALS patients harboring mutations in the gene that codes for a 43 kD TAR DNA-binding protein (TDP-43) exhibit aggregated proteins within affected motor neurons. Current data suggests that these aggregates contain the TDP-43 protein and this aggregation is connected to disease pathology. Cells have evolved a quality control system called proteostasis, which consists of a suite of molecular chaperones that prevents protein misfolding, maintaining a functional proteome. To examine whether a disruption in proteostasis leads to TDP-43 related neurotoxicity, we have established a C. elegans model that expresses human TDP-43 fused to a yellow fluorescent protein (YFP) under the control of a pan-neuronal promoter. Using well-established behavioral assays, we found that TDP-43 animals have reduced egg laying rates, decreased motility, and lowered chemosensory and mechanosensory detection compared to wild type suggesting defects in neuronal functionality. To assess whether these defects are due to neurodegeneration, we visualized the morphological integrity of specific motor and sensory neurons using fluorescence microscopy. We found that loss of neuronal functionality is not due to observable changes in neuronal structure. To test whether neuronal dysfunction is linked to perturbations in proteostasis, we altered chaperone levels by introducing extra copies of hsf-1 and a mutant allele of hsf-1(sy441) into tdp-43 trasngenic animals. Data generated from behavioral assays suggest that imbalances in proteostasis contribute to the neuronal dysfunction associated with TDP-43 expression.