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Defying the Odds: Cell Stress Resistance, CREB, and Neuroprotection in Excitotoxicity 
Stroke / brain ischemia is caused by toxic accumulation of Glutamate
(Glu), leading to excitotoxic neurodegeneration. Glu is toxic to many
brain cells throughout development and aging. However, researchers
observed an increased susceptibility, where aged neurons are far more
likely than young neurons to die following Glu insult. Currently we
know very little about the workings of the internal clock that
triggers a concerted decline of many body systems during aging. We do
not know why older neurons seem to be more fragile and susceptible to
excitotoxicity.Exciting new research of an evolutionary-conserved mechanism of cellular aging and stress resistance is currently emerging. Age-defying mutations in the Insulin/IGF-1 Signaling (IIS) cascade identified in worms were also shown to protect them from cell stress and toxic proteins by activating a cell-protective transcriptional program regulated by the transcription factor FoxO/DAF-16. These effects are also seen in mammals, since the cellular-aging/stress resistance signaling pathways are highly conserved from worms to humans. We ask if the increased cell resistance seen in age-defying mutant nematodes also protects them from Glu-accumulation-triggered excitotoxic neurodegeneration. The availability of particularly powerful research tools in C. elegans, the rich repertoire of aging-affecting mutations, and the advanced understanding of aging signaling pathways in the worm, together with our recent demonstration of excitotoxicity model in this system, make C. elegans the system of choice to study the connection between aging and susceptibility to excitotoxic neurodegeneration. We use pharmacological and genetic analysis to look for processes that affect cellular aging/stress resistance and the susceptibility to excitotoxicity. We have recently found that the Cytohesin/GRP-1 complex regulates the IIS cascade to control the neuroprotective activity of FoxO/DAF-16 in excitotoxic necrosis. We also found that another classic transcription factor, CREB, also controls neuroprotection. We are currently studying how the signaling cascades that control there two transcription factors might cooperate to provide specificity in neuroprotection from excitotoxic necrosis.   |
Physiol. Pharm. & Neurosci, City College, C. elegans @ CUNY