Date on Master's Thesis/Doctoral Dissertation

8-2016

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Hetman, Michal

Committee Co-Chair (if applicable)

States, J. Christopher

Committee Member

States, J. Christopher

Committee Member

Ellis, Steven

Committee Member

Beverly, Levi

Committee Member

Gozal, Evelyne

Author's Keywords

Neurodegenerative Disease; Nucleolus; Ribosomal Biogenesis; Nucleolar Stress; Ribosomal Stress; Ribosomal Protein L11

Abstract

The overarching goal of my studies was to determine the role of the nucleolus in neurodegenerative disease. Numerous studies suggest the impairment of ribosomal biogenesis in neurodegenerative disease and such a condition may contribute to neuronal dysfunction in two ways, loss of function and stress response. Ribosomal biogenesis has been demonstrated to play an essential role in both neuronal growth and maintenance. Therefore insufficient levels of ribosomal biogenesis would be expected to produce atrophy and synapse loss. Moreover, the fidelity of ribosomal biogenesis is monitored by nucleolar and ribosomal stress responses which induce apoptosis and/or cell cycle arrest. Therefore, I have reviewed the literature demonstrating nucleolar involvement in neurodegeneration and investigated three important aspects of nucleolar dysfunction which are relevant to both general mechanisms of neuronal death and specifically neurodegenerative disease. The studies contained in this document address four important questions regarding the nucleolus and neurodegeneration. First, is rDNA content stable throughout aging? Second, is increased rDNA promoter methylation specific to Alzheimer’s disease? Third, are human brain tissue-based assessments of nucleolar stress mechanistically feasible? Fourth, is RPL11 a bona fide nucleolar and ribosomal stress mediator in primary cortical neurons? I demonstrate several important results. rDNA content is stable throughout aging and increased rDNA promoter methylation appears to be specific to Alzheimer’s disease. Nucleolar stress markers are at least moderately stable in the mammalian post mortem brain. Lastly, RPL11 is indeed a bona fide mediator of nucleolar stress, ribosomal stress and neuronal death. Three conclusions contained in this document provide a foundation for future studies investigating nucleolar and ribosomal stress in neurodegenerative disease. First, I provided weight of evidence support for the validity of post mortem brain tissue-based studies. Second, the identification of bona fide stress mediators is an essential step for designing novel therapeutic interventions. Lastly, my results suggest that in primary neurons RPL11-mediated stress does not require catastrophic inhibition of RNA Polymerase I. Therefore, RPL11-mediated stress may indeed be a significant contributor to neurodegeneration despite the lack of canonical nucleolar stress markers.

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