Cell death in the CNS has several unique features stemming from the special characteristics of excitable cells. I have a longstanding interest in excitotoxic and oxidative neuronal death, and in particular, the role of bioenergetics in these processes. A current focus of my work is the ubiquitous nuclear enzyme, poly(ADP-ribose polymerase-1 (PARP-1). PARP-1 is an enzyme that normally functions in DNA repair, but which also mediates bioenergetic failure during excitotoxic and oxidative cell death. PARP activation is also an important mediator of microglial activation, and hence brain inflammation, by virtue of its interaction with NF-ΚB. A major aim of my research program is to elucidate the bioenergetic events between activation of PARP and cell death under disease conditions in brain. A related question concerns the cellular origin of oxidative stress that activates PARP-1. Oxidant production in neurons is widely attributed to the mitochondria, but NADPH oxidase can be the major source of reactive oxidants under some conditions. NADPH oxidase requires glucose to regenerate NADPH substrate, thus forming another intriguing link to cell bioenergetics. A second source of oxidative stress is impaired oxidant scavenging. We have identified the "glutamate" transporter EAAT3 as the major route of neuronal cysteine uptake. Mice that lack EAAT3 have reduced glutathione levels in neurons and undergo age-dependent neurodegeneration and cognitive impairment. The dopaminergic neurons of the substantia nigra are particularly affected. These studies are germane to Parkinson's disease, ischemia, and other conditions in which oxidative stress contributes to neuronal demise.

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