TDP-43 Modulation of PABP Positive, RNA Stress Granule Formation during Oxidative Stress

Persistent Link:
http://hdl.handle.net/10150/579304
Title:
TDP-43 Modulation of PABP Positive, RNA Stress Granule Formation during Oxidative Stress
Author:
Lockwood, Donovan Blair
Issue Date:
2015
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:
RNA dysregulation is a recently recognized disease mechanism in amyotrophic lateral sclerosis (ALS). ALS is a neurodegenerative disease characterized by muscle atrophy and death of both upper and lower motor neurons. A key feature of the disease is the mislocalization of the RNA binding protein TDP-43 and formation of TDP-43 containing cytoplasmic aggregates in motor neurons and surrounding glia. TDP-43 is known to associate with stress granules, and recent studies in mammalian cell culture have indicated that pathological TDP-43 aggregates may arise from RNA stress granules following prolonged stress. We set out to test this hypothesis by investigating the interaction between PolyA Binding Protein (PABP), a known core RNA stress granule component, and TDP-43. Here we show that PABP colocalizes with TDP-43 in a variant dependent manner. Given that the highest risk factor for ALS is aging, an attractive model is that age-related oxidative stress triggers formation of toxic cytoplasmic aggregates from TDP-43 containing stress granules. We have therefore begun investigations using a time course, and live imaging of RNA stress granules under oxidative stress to determine if this leads to an altered RNA stress granule dynamics in cultured motor neurons. These studies will yield a better understanding of the mechanisms that lead to the toxic cytoplasmic aggregates in cases of ALS.
Type:
text; Electronic Thesis
Degree Name:
B.S.
Degree Level:
bachelors
Degree Program:
Honors College; Neuroscience and Cognitive Science - Neurobiology
Degree Grantor:
University of Arizona
Advisor:
Zarnescu, Daniela

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleTDP-43 Modulation of PABP Positive, RNA Stress Granule Formation during Oxidative Stressen_US
dc.creatorLockwood, Donovan Blairen
dc.contributor.authorLockwood, Donovan Blairen
dc.date.issued2015en
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.abstractRNA dysregulation is a recently recognized disease mechanism in amyotrophic lateral sclerosis (ALS). ALS is a neurodegenerative disease characterized by muscle atrophy and death of both upper and lower motor neurons. A key feature of the disease is the mislocalization of the RNA binding protein TDP-43 and formation of TDP-43 containing cytoplasmic aggregates in motor neurons and surrounding glia. TDP-43 is known to associate with stress granules, and recent studies in mammalian cell culture have indicated that pathological TDP-43 aggregates may arise from RNA stress granules following prolonged stress. We set out to test this hypothesis by investigating the interaction between PolyA Binding Protein (PABP), a known core RNA stress granule component, and TDP-43. Here we show that PABP colocalizes with TDP-43 in a variant dependent manner. Given that the highest risk factor for ALS is aging, an attractive model is that age-related oxidative stress triggers formation of toxic cytoplasmic aggregates from TDP-43 containing stress granules. We have therefore begun investigations using a time course, and live imaging of RNA stress granules under oxidative stress to determine if this leads to an altered RNA stress granule dynamics in cultured motor neurons. These studies will yield a better understanding of the mechanisms that lead to the toxic cytoplasmic aggregates in cases of ALS.en
dc.typetexten
dc.typeElectronic Thesisen
thesis.degree.nameB.S.en
thesis.degree.levelbachelorsen
thesis.degree.disciplineHonors Collegeen
thesis.degree.disciplineNeuroscience and Cognitive Science - Neurobiologyen
thesis.degree.grantorUniversity of Arizonaen
dc.contributor.advisorZarnescu, Danielaen
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