Event Title

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

Location

Alumni Hall South

Department

Biology

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. Student Center for Science Engagement, College of Arts and Sciences at Northeastern Illinois University, and U.S. Department of Education (USDOE) Title III Award (P031C160209) supported this research.

Faculty Sponsor

Cindy Voisine, Northeastern Illinois University

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May 6th, 11:20 AM

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

Alumni Hall South

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. Student Center for Science Engagement, College of Arts and Sciences at Northeastern Illinois University, and U.S. Department of Education (USDOE) Title III Award (P031C160209) supported this research.