Date of Award

12-1-2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

Rebecca L. Cunningham

Second Advisor

Meharvan Singh

Third Advisor

Derek Schreihofer

Abstract

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress, mitochondrial dysfunction, inflammation and apoptosis are mechanisms implicated in Parkinson’s pathology. Interestingly, males have a higher incidence of PD than females. Therefore, the major male sex hormone, testosterone may play a role in oxidative stress-induced dopamine neurodegeneration and thus underlie the sex bias observed in PD. Oxidative stress, the imbalance of antioxidant mechanisms and reactive oxygen species, mediates downstream signaling of mitochondria dysfunction, inflammation and apoptosis. Oxidative stress can induce mitochondria dysfunction via calcium neurotoxicity, and oxidative stress can stimulate the pro-inflammatory mediators of NFkB and COX2. This activation of mitochondrial dysfunction and inflammation can trigger apoptosis in dopaminergic neurons. Therefore, it is hypothesized that under oxidative stress conditions, testosterone will induce dopaminergic neurodegeneration by increasing mitochondrial dysfunction and inflammation, leading to apoptosis in dopamine neurons. To test this hypothesis, a N27 dopaminergic cell line was treated with tert-butyl hydrogen peroxide followed by exposure to physiologically relevant concentrations of testosterone to assess cell viability, mitochondria function, calcium influx, inflammation, oxidative stress and apoptosis. These results show that testosterone, alone, increase calcium influx and acts as an oxidative stressor without affecting cell viability. However, under conditions of oxidative stress, testosterone decreases cell viability and exacerbates inflammation, resulting in increased apoptosis. These results indicate that testosterone, only in an oxidative stress environment, can increase pathological features associated with dopamine neurodegeneration in PD. In conclusion, these results suggest that a testosterone mediated mechanism may underlie the increased risk of PD for men compared to women.

Comments

Holmes, Shaletha S., THE EFFECTS OF OXIDATIVE STRESS AND TESTOSTERONE ON DOPAMINE NEURON VIABILITY: IMPLICATIONS FOR PARKINSON’S DISEASE. Doctor of Philosophy (Biomedical Sciences), September, 2015, 150 pp. 2 tables, 34 illustrations, bibliography, 399 titles.

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