The Effects of the Insulin Signaling Pathway on TDP-43 Neurotoxicity in Amyotrophic Lateral Sclerosis

Persistent Link:
http://hdl.handle.net/10150/613411
Title:
The Effects of the Insulin Signaling Pathway on TDP-43 Neurotoxicity in Amyotrophic Lateral Sclerosis
Author:
Riffer, Michelle Kori
Issue Date:
2016
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:
The causes of Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease that results in skeletal muscle paralysis, remain unclear. However, a nuclear DNA and RNA binding protein called TAR DNA binding protein 43 (TDP-43) has emerged as a critical marker of ALS pathology. A previous drug screen conducted in the Zarnescu laboratory showed that anti-diabetic drugs can rescue lethality in a fruit fly model of ALS based on TDP-43. These results suggested that the insulin signaling pathway might be altered in motor neurons in a TDP-43 dependent manner. Therefore, we hypothesized that the insulin pathway is interacting with TDP-43 in vivo and may be contributing to TDP-43neurotoxicity. Using genetic interaction approaches in flies we found that TDP-43dependent locomotor defects are sensitive to the levels of insulin receptor activity. In addition, genetic interaction data suggest that Akt is hyperactivated in motor neurons expressing TDP-43, possibly as a compensatory mechanism to enable survival. Finally, upregulating protein synthesis through S6K and 4EBP appears to have beneficial effects. These findings support our hypothesis and provide insights into potential therapeutic strategies to help treat this devastating disease.
Type:
text; Electronic Thesis
Keywords:
Insulin Signaling; Larvae; Neurotoxicity; TDP-43; Molecular & Cellular Biology; Amyotrophic Lateral Sclerosis
Degree Name:
M.S.
Degree Level:
masters
Degree Program:
Graduate College; Molecular & Cellular Biology
Degree Grantor:
University of Arizona
Advisor:
Zarnescu, Daniela C.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleThe Effects of the Insulin Signaling Pathway on TDP-43 Neurotoxicity in Amyotrophic Lateral Sclerosisen_US
dc.creatorRiffer, Michelle Korien
dc.contributor.authorRiffer, Michelle Korien
dc.date.issued2016-
dc.publisherThe University of Arizona.en
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
dc.description.abstractThe causes of Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease that results in skeletal muscle paralysis, remain unclear. However, a nuclear DNA and RNA binding protein called TAR DNA binding protein 43 (TDP-43) has emerged as a critical marker of ALS pathology. A previous drug screen conducted in the Zarnescu laboratory showed that anti-diabetic drugs can rescue lethality in a fruit fly model of ALS based on TDP-43. These results suggested that the insulin signaling pathway might be altered in motor neurons in a TDP-43 dependent manner. Therefore, we hypothesized that the insulin pathway is interacting with TDP-43 in vivo and may be contributing to TDP-43neurotoxicity. Using genetic interaction approaches in flies we found that TDP-43dependent locomotor defects are sensitive to the levels of insulin receptor activity. In addition, genetic interaction data suggest that Akt is hyperactivated in motor neurons expressing TDP-43, possibly as a compensatory mechanism to enable survival. Finally, upregulating protein synthesis through S6K and 4EBP appears to have beneficial effects. These findings support our hypothesis and provide insights into potential therapeutic strategies to help treat this devastating disease.en
dc.typetexten
dc.typeElectronic Thesisen
dc.subjectInsulin Signalingen
dc.subjectLarvaeen
dc.subjectNeurotoxicityen
dc.subjectTDP-43en
dc.subjectMolecular & Cellular Biologyen
dc.subjectAmyotrophic Lateral Sclerosisen
thesis.degree.nameM.S.en
thesis.degree.levelmastersen
thesis.degree.disciplineGraduate Collegeen
thesis.degree.disciplineMolecular & Cellular Biologyen
thesis.degree.grantorUniversity of Arizonaen
dc.contributor.advisorZarnescu, Daniela C.en
dc.contributor.committeememberSchwartz, Jacoben
dc.contributor.committeememberNagy, Lisaen
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