Increasing evidence suggests that oxidative damage plays a substantial role in many neurological diseases, as well as in apoptosis associated with the aging process. However, the specific mechanism by which oxidative stress contributes to apoptosis is presently unknown. In sympathetic neurons, free oxygen radical formation occurs within four hours after nerve growth factor (NGF) withdrawal. Further, the production of these reactive oxygen species (ROS) is necessary and appears to serve as an early signal to trigger the apoptotic pathway in neurons. NADPH oxidase is an enzyme known to produce significant ROS levels in non-neuronal cell types. Current dogma suggests that the expression of functional NADPH oxidase is limited to non-neuronal cells. However, from preliminary data, we have evidence that NADPH oxidase, or an enzyme that is NADPH oxidase-like, is present in sympathetic neurons at both the mRNA and protein levels. Further, neurons from NADPH oxidase-deficient mice exhibit delayed death following NGF deprivation. Based on these data, we hypothesize that an NADPH oxidase produces a significant portion of the ROS essential for apoptosis in trophic facto: deprived sympathetic neurons. The work proposed here is highly novel given that the presence of NADPH oxidase in neurons has not been established, much less its contribution(s) to neuronal apoptosis. Since oxidative stress has been implicated in neurodegenerative diseases, as well as stroke, and aging, elucidating the role of NADPH oxidase and the means to modulate this activity in neuronal death may contribute to eventual treatment modalities.
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