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Oxidative Damage and Selective Neuronal Vulnerability in Alzheimer's Disease

Welty, Jacqueline (2019) Oxidative Damage and Selective Neuronal Vulnerability in Alzheimer's Disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Human cells are constantly under assault by damaging agents that arise from endogenous and exogenous sources. Damage to DNA is especially harmful because it encodes essential RNA molecules and proteins necessary for cellular functions. Failure to carry out sufficient DNA repair may compromise the genome and lead to the development of mutations and potential disease. Specifically, oxidative damage in the form of reactive oxygen species (ROS) and resulting DNA double strand breaks (DSBs) have been implicated in neurodegenerative diseases such as Alzheimer’s Disease (AD). Many cells, such as epithelial cells, are constantly replaced and do not need robust systems of repair. However, terminally differentiated and post-mitotic cells such as neurons must survive a lifetime and maintain genomic stability. How they manage to do so is still under investigation.
For error-free repair of DSBs, homologous recombination (HR) can occur during the S/G2 phases of the cell cycle utilizing a sister chromatid template. However, for post-mitotic cells such as neurons that cannot utilize a sister chromatid template, only the error-prone non-homologous end joining (NHEJ) pathway has been proposed. Recent studies in my lab have elucidated a novel RNA-templated recombination based repair pathway that occurs in the G0/G1 phase of the cell cycle. How post-mitotic terminally differentiated neuronal cells utilize these pathways has yet to be understood.
The goal of my thesis is to understand how post-mitotic neurons maintain genomic integrity in repairing DSBs when faced with excessive oxidative damage. My preliminary studies have shown recruitment of transcription coupled homologous recombination (TC-HR) factor RAD52 to sites of DSB induced by laser microirradiation in primary post-mitotic rat cortical neuronal cells. This recruitment is largely dependent upon active transcription. How neurons utilize TC-HR proteins in DSB repair has yet to be elucidated. My main hypothesis is that terminally differentiated post-mitotic neurons utilize the TC-HR pathway to repair DSBs and maintain genomic integrity. To test this hypothesis, I investigated the roles of TC-HR associated proteins in post-mitotic neurons and how toxic soluble amyloid beta (A1-42) oligomers compromise this pathway, which may lead to neurodegenerative pathologies seen in AD.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Welty, Jacquelinestarr.welty@me.comjaw2270000-0003-1581-4763
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairYanowitz, Judithyanowitzjl@mwri.magee.edu0000-0001-6886-8787
Committee MemberThomas, Garythomasg@pitt.eduthomas
Committee MemberYu, Jianyuj2@upmc.edu0000-0002-4021-1000
Committee MemberShair, KathyKAS361@pitt.eduKAS3610000-0002-9556-1745
Committee MemberThathiah, Amanthaamantha@pitt.eduamantha0000-0002-3132-4409
Thesis AdvisorTsang, Michaeltsang@pitt.edutsang0000-0001-7123-0063
Date: 7 May 2019
Date Type: Publication
Defense Date: 9 April 2019
Approval Date: 7 May 2019
Submission Date: 16 April 2019
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 135
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Genetics and Developmental Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Alzheimer's Disease, TC-HR, DNA repair, neurodegeneration, amyloid beta, DNA damage
Date Deposited: 07 May 2019 18:54
Last Modified: 07 May 2019 18:54


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