Free radicals and their reactive metabolites (reactive oxygen species [ROS]) exist in neuronal cells and tissues at low but measurable concentrations (1
). These tolerable equilibrium concentrations are the result of a tightly controlled balance between the rates of production and clearance, the latter being mediated by a team of antioxidants including enzymes and nonenzymatic compounds such as the tripeptide glutathione.
Cells or tissues are in a stable oxidative state if the rates of ROS production and scavenging capacity remain within a homeostatic range. However, if this balance is disturbed, either by an increase in ROS concentrations or a decrease in antioxidant activities, the response may not be sufficient to keep the system at a level compatible with survival. In such cases, oxidants can modify cellular targets, leading to cell dysfunction or death (2
). Indeed, oxidative stress has been implicated in virtually all of the major acute and chronic neurodegenerative diseases (3
In many cells, including cortical neurons, the expression of genes with antioxidative activity is precisely controlled by a synergistic network of redox-sensing signaling cascades (4
). Specifically, aberrant levels of oxidants can trigger the transcriptional induction of antioxidative enzymes and other adaptive pathways (5
). The cellular response to oxidative stress is tightly controlled by a family of stress-responsive transcription factors (2
). Among these transcription factors, the activating transcription factor 4 (ATF4)/cAMP response element binding protein 2 may be a key player (7
). ATF4 is expressed constitutively only at low concentrations but becomes rapidly induced under particular cell-stress conditions (10
). ATF4 binds to the promoter regions of an array of different target genes, including many involved in amino acid metabolism and redox control (11
). In fibroblasts, ATF4 coordinates the response to amino acid depletion, oxidative stress, and endoplasmic reticulum stress, and helps to balance redox homeostasis. Indeed, ATF4-deficient fibroblasts have been shown to be prone to death after a host of stresses, including oxidative stress and amino acid deprivation (11
Interestingly, amino acid deprivation has been previously reported to be neuroprotective in an in vitro model of oxidative stress–induced cell death (12
). This model employs immature cortical neurons and takes advantage of the absence of glutamate receptors at this stage of development to avoid excitotoxicity. Instead, addition of glutamate analogues competitively inhibits uptake of cyst(e)ine, the rate-limiting precursor for the tripeptide glutathione. The resulting decline in glutathione concentration is a primary event that leads to neuronal cell death from oxidative stress (13
), a process that displays many features of apoptosis (14
). This glutathione depletion model facilitates the separation of biochemical events that mediate death from those that are a consequence of death, and it is highly relevant to pathological conditions because an increase in cellular ROS production is often observed in apoptotic processes triggered by diverse stimuli associated with disease states. In this work, we define a novel prodeath role for ATF4 in neurons in vitro in response to oxidative stress and in vivo in response to stroke, a condition linked to oxidative stress.