Programmed cell life: anti-apoptotic signaling and therapeutic strategies for neurodegenerative disorders

Injury to the nervous system initiates a cascade of signal transduction events that mobilize survival-promoting gene products and post-translational modifications of existing proteins involved in neuronal injury responses. These 'cell life programs' appear to converge on gene products involved in maintenance of calcium homeostasis and suppression of free radical accumulation. Central to the hypothesis of 'programmed cell life' is that neurons die (either by apoptosis or necrosis) when the severity or duration of the insult overcomes the ability of the cell life programs to protect the cell. Whether cell death manifests as apoptosis or necrosis depends upon the severity and duration of the insult, the cell type encountering the insult, and the state of the cell rather than the type of insult. For example, activation of glutamate receptors and oxidative insults can kill neurons by a rapid necrotic mode or a delayed apoptotic mode. In either case, calcium and free radicals mediate the cell injury. Several categories of anti-apoptotic signaling molecules (AASMs) are released from neurons and/or glia in response to brain injury including: classic neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor and basic fibroblast growth factor; cytokines such as tumor necrosis factor and interleukin-1; protease inhibitors such as protease nexin-1; and novel AASMs such as secreted forms of the β-amyloid precursor protein. The specific ways in which AASMs promote cell survival range from induction of antioxidant enzymes to regulation of glutamate receptor expression to stimulation of calcium-binding protein expression to activation of K+ channels. The intracellular messengers mediating programmed cell life pathways include intermediate kinases. cyclic nucleotides and transcription factors such as NFκB. As details of AASM signal transduction pathways emerge so do novel therapeutic approaches to reducing neuronal degeneration. Because neuronal degeneration in many, if not all, neurodegenerative conditions results from excessive accumulation of free radicals and disruption of calcium homeostasis, activiation of AASM signaling pathways has broad applicability to both acute and chronic neurodegenerative disorders.