An increased production of reactive oxygen species is thought to be critical to the pathogenesis of Parkinson's disease. Furthermore, a growing body of evidence indicates that alterations in the glutathione system, and specifically the detoxification of hydrogen peroxide by glutathione peroxidase (GPx), may play a central role in the development of this oxidative stress. In this study, we will use GPx knockout (GPxKO) mice and recombinant adenoviruses to examine the significance of GPx and glutathione (GSH) to the survival of dopaminergic neurons. In addition, we will investigate how adding the putative exogenous source of free radical 1-methyl-4-phenylpyridine affects the role of GPx in handling oxidative stress in dopaminergic neurons. We will begin by examining the survival of dopaminergic neurons in dissociated mesencephalic cultures which are designed to minimize glial contamination. In addition, we will use digital imaging microfluorimetry to measure levels of free radicals and GSH in individual dopaminergic and nondopaminergic neurons. Subsequently, we will use an in vivo paradigm to study the GSH system in a more physiologic environment.
| Nakamura, K; Wright, D A; Wiatr, T et al. (2000) Preferential resistance of dopaminergic neurons to the toxicity of glutathione depletion is independent of cellular glutathione peroxidase and is mediated by tetrahydrobiopterin. J Neurochem 74:2305-14 |
