Research Program Cell death in the CNS has several unique features stemming from the special characteristics of excitable cells. We have a longstanding interest in excitotoxic and oxidative neuronal death, and in particular, the role of bioenergetics and inflammation in these processes. One focus of our work is the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP-1). PARP- 1 normally functions in DNA repair, but additionally mediates bioenergetic failure during excitotoxic and oxidative cell death. PARP-1 activation is also an important mediator of microglial activation, and hence brain inflammation, by virtue of its interaction with the transcription factor NF-?B. We aim to elucidate the links between bioenergetic changes, PARP-1 activation, and brain inflammation. A related question concerns the cellular origin of oxidative stress in brain. Oxidant production in neurons is widely attributed to the mitochondria, but NADPH oxidase can be the major source of reactive oxidants under some conditions. We are working to establish the signal transduction steps linking glutamate receptor activation to activation of NADPH oxidase in neurons. 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. We are evaluating ways to augment neuronal glutathione production as a potential therapeutic approach to Parkinson’s disease and other disorders in which oxidative stress contributes. The accumulation of somatic DNA mutations may be a common pathway in chronic oxidative stress, inflammation, and neurodegenerative disorders. In collaboration with Dr. Jan Vijg, we are evaluating this hypothesis using transgenic mice with reporter genes for nuclear DNA damage. These studies may help identify the proximate cause of neuronal death in neurodegenerative disorders.