Membrane androgen receptor-induced oxidative stress: mechanism involved in neurodegeneration

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. 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.