Abstract
During ischemic stroke, malfunction of excitatory amino acid transporters and reduced synaptic clearance causes accumulation of Glutamate (Glu) and excessive stimulation of postsynaptic neurons, which can lead to their degeneration by excitotoxicity. The balance between cell death-promoting (neurotoxic) and survival-promoting (neuroprotective) signaling cascades determines the fate of neurons exposed to the excitotoxic insult. The evolutionary conserved Insulin/IGF Signaling (IIS) cascade can participate in this balance, as it controls cell stress resistance in nematodes and mammals. Blocking the IIS cascade allows the transcription factor FoxO3/DAF-16 to accumulate in the nucleus and activate a transcriptional program that protects cells from a range of insults. We study the effect of IIS cascade on neurodegeneration in a C. elegans model of excitotoxicity, where a mutation in a central Glu transporter (glt-3) in a sensitizing background causes Glu-Receptor –dependent neuronal necrosis. We expand our studies on the role of the IIS cascade in determining susceptibility to excitotoxic necrosis by either blocking IIS at the level of PI3K/AGE-1 or stimulating it by removing the inhibitory effect of ZFP-1 on the expression of PDK-1. We further show that the components of the Cytohesin/GRP-1, Arf, and PIP5K/PPK-1 complex, known to regulate PIP2 production and the IIS cascade, modulate nematode excitotoxicity: mutations that are expected to reduce the complex's ability to produce PIP2 and inhibit the IIS cascade protect from excitotoxicity, while overstimulation of PIP2 production enhances neurodegeneration. Our observations therefore affirm the importance of the IIS cascade in determining the susceptibility to necrotic neurodegeneration in nematode excitotoxicity, and demonstrate the ability of Cytohesin/GRP-1, Arf, and PIP5K/PPK-1 complex to modulate neuroprotection.
Highlights
Stroke/brain ischemia is the fourth leading cause of death in the US [1]
We find the Cytohesin/ Arf/PIP5K complex to be relevant to our study of excitotoxicity because its components have been associated with the Post Synaptic Density (PSD) that orchestrates intracellular signaling complexes associated with Glu Receptors (GluRs)
A number of studies in mammalian cells suggest that blocking the Insulin/IGF Signaling (IIS) cascade and AKT activation enhances neuronal apoptosis in excitotoxicity [4, 69,70,71,72,73], while our previous studies in both nematodes and mouse neuronal cultures suggest that blocking the IIS cascade reduces excitotoxic necrosis [44]
Summary
Stroke/brain ischemia is the fourth leading cause of death in the US [1]. Current therapeutic interventions have very limited success, and pharmacological trials based on previous understanding of the neurodegenerative process ended with disappointment [2,3,4,5]. Waves of destruction propagate from the acute center of injury to cause cell death by necrosis and apoptosis, while in the penumbra (the area surrounding the ischemic core), neurons that are initially ‘‘stunned’’ might later die or recover [6,7,8,9]. The clearance of Glu by secondary-active Glu transporters (GluTs) declines [11,12,13,14], causing synaptic Glu accumulation, overstimulation of ionotropic Glu Receptors (GluRs), and a large influx of Ca2+ that might lead to neurodegeneration in a process termed excitotoxicity [4, 15,16,17,18]. Accumulating evidence indicates that GluR activation contributes to both cell death and neuroprotection [2, 4], but our understanding of both Glu-induced and Gluindependent mechanisms of neuroprotection remains incomplete. We are interested in identifying neuroprotective mechanisms that might regulate the susceptibility of neurons to excitotoxicity
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