Using c. elegans to uncover the link between the cellular unfolded protein response and TDP-43 proteotoxicity

Abstract

Neurodegenerative diseases are categorized by deterioration of nerve cells and chronic progression of fatal symptoms. A hallmark of these diseases is the aggregation of specific proteins in affected neurons. TAR DNA Binding Protein 43 (TDP-43) is found in aggregates in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and more. Cells possess an evolutionarily conserved system that normally prevents protein aggregation called proteostasis. However, in these diseases, this system no longer functions properly. To study the link between proteostasis and TDP-43 related toxicity, we are using the small, transparent nematode, Caenorhabditis elegans. In the Voisine lab, a transgenic line expressing human TDP-43 expressed in the nervous system has already been generated. Using this transgenic line, I will perform a genetic cross to introduce a deletion of catp-3 (Δcatp-3). This gene encodes for a protein product that is predicted to enable the unfolded protein response (UPR), a proteostatic system that is responsible for maintaining proteostasis within the endoplasmic reticulum (ER) by responding to accumulation of unfolded or misfolded proteins. Once this new strain is generated, I will examine the physiological effects of disrupting proteostasis of TDP-43 toxicity. Using a well-established behavioral assay called a thrashing assay, I will measure the movement of the worms in liquid to assess motor neuron function. I hypothesize that removing the catp-3 gene will improve motor neuron function in worms expressing TDP-43. Observing the behavioral effects of Δcatp-3 would provide insight into the role of proteostasis in neurodegenerative pathology