Publication Date

2012-08-08

Availability

Embargoed

Embargo Period

2014-08-08

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2012-04-06

First Committee Member

Carlos T. Moraes

Second Committee Member

Gavriel David

Third Committee Member

Antonio Barrientos

Fourth Committee Member

Giovanni Manfredi

Fifth Committee Member

Stephan Zuchner

Abstract

Mitochondrial DNA (mtDNA) damage and oxidative phosphorylation deficiency have been associated with neurodegenerative disease and aging. I hypothesized that different neuronal populations handle the respiratory chain dysfunctions differently and that different cell types also mediate different responses to mtDNA damage. We used a transgenic mouse model under the tetracycline response system to temporally and spatially control the expression of a mitochondrial-targeted restriction endonuclease, mito-PstI. Using different neuronal drivers to induce the expression of mito-PstI, we were able to elicit mtDNA double strand break damage causing an OXPHOS deficiency in vivo (Chapter 2 and 3). We then were able to follow the progressive neurodegenerative events as a result of the mitochondrial dysfunction to discover that certain neuroanatomical regions were more susceptible to OXPHOS deficiency (Chapter 2). We also observed that mitochondrial dysfunction selectively impairs axonal processes before cell bodies leading to behavioral deficits prior to complete neuronal demise (Chapter 3). Finally, we developed a ubiquitous systemic model under the Rosa26 promoter to examine how different cell types handle transient mtDNA damage (Chapter 4). Our animals had a progressive premature aging phenotype; however, we could not attribute our phenotypes to the mtDNA deletions commonly thought to participate in the aging process. We discovered a novel p53 transcriptional response after mtDNA damage that may directly or partially account for the cellular senescence present in these mice later in life. In conclusion, we demonstrate that mitochondrial decline and mtDNA damage impacts different cell types in different ways. Future studies need to concentrate on how other neuronal and glial cell types are impacted by mitochondrial decline, and how p53 signals from the mitochondria to the nucleus.

Keywords

Mitochondria; Striatum; Oxidative Phosphorylation; Mitochondrial DNA; p53; Parkinson's disease

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