Investigating the Functional Interaction Between TDP-43 and FMRP in a Drosophila Melanogaster Model of Neurodegeneration

Persistent Link:
http://hdl.handle.net/10150/297591
Title:
Investigating the Functional Interaction Between TDP-43 and FMRP in a Drosophila Melanogaster Model of Neurodegeneration
Author:
Gopalakrishnan, Siddesh
Issue Date:
2013
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Amyotrophic 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.
Type:
text; Electronic Thesis
Degree Name:
B.S.
Degree Level:
bachelors
Degree Program:
Honors College; Molecular and Cellular Biology
Degree Grantor:
University of Arizona
Advisor:
Zarnescu, Daniela

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleInvestigating the Functional Interaction Between TDP-43 and FMRP in a Drosophila Melanogaster Model of Neurodegenerationen_US
dc.creatorGopalakrishnan, Siddeshen_US
dc.contributor.authorGopalakrishnan, Siddeshen_US
dc.date.issued2013-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.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.en_US
dc.typetexten_US
dc.typeElectronic Thesisen_US
thesis.degree.nameB.S.en_US
thesis.degree.levelbachelorsen_US
thesis.degree.disciplineHonors Collegeen_US
thesis.degree.disciplineMolecular and Cellular Biologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorZarnescu, Daniela-
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