Investigating the Functional Interaction Between TDP-43 and FMRP in a Drosophila Melanogaster Model of Neurodegeneration
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PublisherThe University of Arizona.
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AbstractAmyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by loss of motor neuron function. This disease can lead to paralysis and respiratory failure followed by death. TDP-43, TAR DNA binding protein, is a major disease protein found in ALS patients. In patients with the disease, mutant TDP-43 levels disrupt various cellular processes and create neurotoxicity in motor neurons as well as glia. TDP-43 interacts with Fragile X Mental Retardation Protein (FMRP) in cytoplasmic stress granules. FMRP has numerous molecular protein targets including futsch and profilin. Published data shows that loss of FMRP leads to increased futsch and profilin expression. Conversely, an increase in FMRP expression results in down regulation of Futsch and Profilin levels through translational regulation. In addition, there is also data to suggest that FMRP can regulate the expression of TDP-43. This project was based on the hypothesis that disease causing TDP-43 mutations associate with stress granules and recruit FMRP. This results in less FMRP being available to regulate its translational targets such as futsch and profiling and a subsequent increase in Futsch and Profilin protein levels. This working model predicts that reducing futsch and/or profilin levels will alleviate TDP-43 toxicity. To test this model three main examinations were performed. The first involved characterizing the phenotype of futsch hypomorphs to determine their effect on TDP-43 induced neurodegeneration. The second was to see how futsch and chickadee (Drosophila profilin) levels change with varying levels of FMRP. The third was an examination of human profilin transgenic lines to see whether it leads to neurodegeneration as predicted from its recent linkage to ALS. My work shows thatfutsch and chickadee hypomorphs decrease TDP-43 neurodegeneration, consistent with our working hypothesis.
Degree ProgramHonors College
Molecular and Cellular Biology