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MEMBRANE ANDROGEN RECEPTOR-INDUCED OXIDATIVE STRESS: MECHANISM INVOLVED in NEURODEGENERATION DISSERTATION Presented to the Gradu

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MEMBRANE ANDROGEN RECEPTOR-INDUCED OXIDATIVE STRESS: MECHANISM INVOLVED in NEURODEGENERATION DISSERTATION Presented to the Gradu MEMBRANE ANDROGEN RECEPTOR-INDUCED OXIDATIVE STRESS: MECHANISM INVOLVED IN NEURODEGENERATION DISSERTATION Presented to the Graduate Council of the Graduate School of Biomedical Sciences University of North Texas Health Science Center at Fort Worth in Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY By Mavis A. A. Tenkorang, B (Pharm) Fort Worth, Texas April 2019 i Copyright by Mavis A. A. Tenkorang 2019 ii MEMBRANE ANDROGEN RECEPTOR-INDUCED OXIDATIVE STRESS: MECHANISM INVOLVED IN NEURODEGENERATION Mavis A.A. Tenkorang APPROVED: ……………………………………………………………………………………………………… Major Professor, Rebecca L. Cunningham, Ph.D ……………………………………………………………………………………………………… Committee Member, Sid O’Bryant, Ph.D ……………………………………………………………………………………………………… Committee Member, Derek Schreihofer, Ph.D ……………………………………………………………………………………………………… Committee Member, Robert Barber, Ph.D ……………………………………………………………………………………………………… University Member, YiQiang (Eric) Cheng, Ph.D ……………………………………………………………………………………………………… Chair, Department of Pharmacology & Neuroscience, Michael Forster, Ph.D ……………………………………………………………………………………………………… Dean, J. Michael Mathis, Ph.D, EdD), Graduate School of Biomedical Sciences iii ABSTRACT Oxidative stress-associated neurodegenerative diseases, such as Parkinson’s disease (PD), affect millions of people worldwide. Although aging is the greatest risk factor for PD, other significant factors may be implicated, such as sex hormones that can mediate sex differences. Men have a higher incidence and prevalence of PD than women. Therefore, testosterone, a primary male sex hormone and a known oxidative stressor, is implicated in PD pathophysiology. Since androgens can have negative effects on dopaminergic cells, it is imperative to understand the underlying mechanisms in order to determine what mediates the observed sex differences in PD prevalence. NADPH Oxidase 1 and 2 are major oxidative stress generators in the brain, thus potential targets for testosterone-induced oxidative stress and cell death. This dissertation project therefore investigates the role of androgens and membrane androgen receptor activation on NOX1/2. We hypothesize that in dopaminergic cells, testosterone activates the membrane androgen receptor (AR45) that is complexed with NOX1/2 to increase oxidative stress. In an oxidative stress environment, androgen activation of this AR45-NOX complex leads to cell death. Results indicate that classical androgen receptor (AR) antagonists do not block testosterone’s negative actions in an oxidative stress environment. The effects of AR45-NOX complex on cell viability can be blocked by either degrading AR45 protein or blocking NOX activation by apocynin. Further, these results show that testosterone’s detrimental effect on cells is via a non-genomic mechanism, specifically via a novel membrane androgen receptor, AR45. iv The findings of this study help identify key players in testosterone-induced neurodegeneration, which could serve as potential therapeutic targets for PD. Ultimately, this project provides novel mechanisms to explain thought provoking questions on male sex bias in PD. v ACKNOWLEDGEMENTS I would like to first and foremost thank the Almighty God for giving me life, strength and wisdom to pursue this course. Without Him, I would not have accomplished this dream. My journey towards this degree has heightened my belief that, indeed, there are angels on earth. I found a mentor, an advisor and a role model in Dr. Rebecca Lynn Cunningham. She gave me her endless support, room to make mistakes in order to learn from experience. I am forever grateful to her. I am highly indebted to my committee members; Dr. Derek Schreihofer, Dr. Robert Barber, Dr. Sid O’Bryant, Dr. Eric Cheng, for wholeheartedly accepting to serve on my committee, and continuously guiding me in the right direction. I made it through this journey due to your collective efforts. Next, I would like to thank the past and present members of the Cunningham lab for their contribution in diverse ways towards my research. I cannot end without acknowledging my biggest source of inspiration; my family. My deepest gratitude goes to my husband; Napthali, my daughter; Gracielle, my parents and siblings, for constantly supporting my dream. To all my friends that rallied behind me, I say a huge thank you. vi TABLE OF CONTENTS Page Acknowledgements……………………………………………………………………………vi List of Tables………………………………………………………………………………….ix List of Illustrations………………………………………………………………………….....ix Specific Aims.………………………………………………………………...…………….....xi CHAPTER 1 a. Sex-Related Differences in Oxidative Stress and Neurodegeneration………………..1 b. Abstract………………………………………………………………………………..2 c. Literature Review………………………………………………………………….......3 d. Conclusion……………………………………………………………………………13 e. Reference List………………………………………………………………………...14 CHAPTER 2 a. Neurodegenerative Diseases ……………..……………..…...……………………….30 b. Androgens ………………………………………………………………....................31 c. Androgen Receptors ……………………………………….……………..……….….31 d. Androgen Receptor Antagonists……………………………………………………...33 e. Androgen Receptor Degrader (ASC-J9)……………………………………………...34 f. Androgens and Oxidative Stress …………………………………………..................34 g. NADPH Oxidase Enzyme …………………………………………............................35 h. Non-Specific NOX Inhibitors………………………………………………………...36 vii i. Selective NOX Inhibitors……………………………………………………………..37 j. NOX Mediated Pathways……………………………………………………………..38 k. NOX and IP3 Receptor………………………………………………………………..38 l. Reference List………………………………………………………………………...40 m. Figures………………………………………………………………………………...51 CHAPTER 3 a. NADPH Oxidase (NOX) Mediates Membrane Androgen Receptor-Induced Neurodegeneration …...................................................................................................54 b. Abstract……………………………………………………………………………….55 c. Introduction…………………………………………………………………………...56 d. Materials and Methods ……………………………………………………………….58 e. Results………………………………………………………………………………...64 f. Discussion …………………………………………………………………………….71 g. Reference List………………………………………………………………………....77 CHAPTER 4 a. Summary Discussion…………………………………………………………………103 b. Clinical Implications………………………………………………………………….105 c. Future Studies ……………………………………………………………..................108 d. Reference List………………………………………………………………………...110 viii LIST OF TABLES CHAPTER 1 TABLE 1: Sample Population Characteristics………………………………………………..26 LIST OF ILLUSTRATIONS CHAPTER 1 Figure 1- Homocysteine Levels (Oxidative Stress) in Cognitively Intact Participants……….28 Figure 2- Homocysteine Levels in AD Patients……………………………………………....29 CHAPTER 2 Figure 1- Androgen Pathways ………………………………………………………………..51 Figure 2- Co-Immunoprecipitation…….……………………………………………………..52 Figure 3- G Protein-Coupled Receptor Signaling Pathway…………………………………..53 CHAPTER 3 Figure 1- Experimental Design……………………………………………………………….89 Figure 2- Co-Immunoprecipitation of AR45, NOX1, NOX2 to Determine Protein Complex………………………………………………………………………………………90 Figure 3- Testosterone’s Detrimental Effects Are Not Mediated Through The Classical Genomic Pathway……………………………………………………………………………………….91 Figure 4- The Role of G Protein and InsP3R Receptor in Testosterone-Induced Neurodegeneration……………………………………………………………………………93 ix Figure 5- The Effects of Non-Specific NOX Inhibitor on Oxidative Stress Generation and Cell Loss……………………………………………………………………………………………95 Figure 6- The Effects of Selective NOX Inhibitors on Testosterone-Induced Cell Loss……. 97 Figure 7- The Effects of AR Degradation on NOX1 and NOX2 Protein Expression………...99 Figure 8- Working Model…………………………………………………………………….101 CHAPTER 4 Figure 1- Feed forward regulation of membrane androgen receptor/NOX complex on oxidative stress generation……………………………………………………………………………...115 x Specific Aims Neurodegenerative diseases, of which Parkinson’s and Alzheimer’s disease are the most prevalent, affect millions of people worldwide. In fact, Parkinson’s disease (PD) has been recorded as the second most common neurological disease. Generally, PD symptoms manifest when 80% of the cells within the substantia nigra are lost. Currently, the etiology of the disease remains elusive. Although aging is the greatest risk factor for PD, other significant factors may be implicated, such as oxidative stress (OS). OS plays a key role in the pathogenesis of PD. Several studies have established that PD is sex biased, affecting more men than women. Testosterone, a primary male sex hormone and a known oxidative stressor, has been implicated in PD. Evolution of science has brought about a drastic improvement in the motor symptoms of PD. Nonetheless, there are still growing controversies in the use of testosterone replacement therapies (TRT) in the management of non-motor symptoms of PD, such as decreased sexual libido and sexual dysfunction. It is unclear whether TRT in men with PD provides any substantial benefit. Previous studies in our lab indicate that testosterone via a non-genomic mechanism exacerbates OS damage in dopaminergic neurons. Specifically, testosterone acts through a membrane associated androgen receptor (mAR) variant – AR45, leading to the activation of OS that can result in cell death. However, the mechanism by which testosterone increases OS is unknown. xi NADPH Oxidase (NOX) is a major OS generator in cells. In fact, both NOX 1 and NOX 2 (NOX 1/2) are associated with OS in dopaminergic cells, hence potential contributors to the pathogenesis of Parkinson’s disease. It is possible that NOX 1/2 complexes with the membrane androgen receptor (AR45) to mediate testosterone-induced
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