Impact of Phosphatase Activity in C. elegans Expressing TDP-43, an Amyotrophic Lateral Sclerosis Associated Disease Protein

Date of Award

5-2023

Document Type

Thesis

Department

Biology

First Advisor

Dr Cindy Voisine

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease. Mutations in the TAR DNA-binding Protein of 43 kDa (TDP-43), an RNA binding protein, have been linked to familial cases of ALS. The accumulation of hyperphosphorylated TDP-43 in the cytoplasm of affected neurons is considered a pathological hallmark of the disease. However, the role of phosphorylation in disease progression remains unclear. To understand the impact of phosphorylated TDP-43 on neuronal function, we are using the nematode C. elegans, a transparent worm that has a short lifespan, a simple nervous system and is amenable to genetic manipulation. Deep sequencing of actively translated mRNAs from adult animals that express human TDP-43 pan-neuronally and wild type animals revealed a set of differentially translated mRNAs. Gene Ontology analysis identified an enrichment of the dephosphorylation biological process suggesting that animals expressing neuronal TDP-43 increase phosphatase activity, possibly to reduce the level of phosphorylated TDP-43. I selected two phosphatase-related genes, one gene is expressed in the nervous system of worms and the second gene has a human orthologue, PTPN7, that participates in MAP-kinase signaling. Currently, I am crossing strains that carry deletions of each phosphatase gene with TDP-43 expressing animals. Using western analysis, I will determine if the deleted phosphatases increase levels of phosphorylated TDP-43. Furthermore, behavioral assays will be conducted to measure neuronal functionality in these animals. These studies offer insight into potential therapeutic strategies targeting TDP-43 phosphorylation to alleviate ALS pathology.

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