xcitotoxicity, while many other studies might involve several death mechanisms or focus on ATL 962 biological activity apoptotic cell death. The condition that we study does not seem to involved apoptosis. The ability of FoxO activation to lead to diverse consequences, depending in the exact combination of cellular factors, is well documented. We therefore suggest the simplified scenario of nematode excitotoxicity, where apoptosis is not involved, allows us to clearly dissect a neuroprotective effect for FoxO/DAF-16, an effect that participates also in the more complex scenarios that take place in mammalian excitotoxicity. In the future, this 
might help us illuminate conserved neuroprotection-specific processes in excitotoxicity downstream of FoxO/DAF-16. The IIS-stimulating complex of GRP-1 & PPK-1 serves to regulate excitotoxicity Our data puts the spotlight on the IIS-regulating Cytohesin/GRP-1, Arf, and PIP5K/PPK-1 complex and its role in regulating susceptibility to excitotoxicity in C. elegans. Using epistasis we demonstrate that grp-1 works in the same pathway as age-1 to regulate neurodegeneration levels. We further show that this effect is unlikely to involve grp-1’s regulation of apoptosis, as apoptosis seems not to be involved in nematode excitotoxicity. It is possible that other IIS cascade-regulated processes might also be influenced by this complex. However, as the focus of our research is excitotoxicity, our data does not address those other functions of the IIS cascade. Together with our previous data on the nuclear translocation of DAF-16 as a means to induce neuroprotection, our studies are therefore in line with a model where the Cytohesin/GRP-1, Arf, and PIP5K/PPK-1 complex controls the transcriptional output of the IIS cascade to regulate susceptibility to excitotoxicity. The GRP-1 & PPK-1 might serve as a link that allows GluR to control neuroprotection and susceptibility to excitotoxicity Our initial interest in the Cytohesin/GRP-1, Arf, and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19689163 PIP5K/PPK-1 complex was based on the studies that indicate its physical association with the PSD and with GluRs. Currently the subcellular localization of this complex is unknown. It also remains to be seen if GluRs provide any PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19690518 input to IIS signaling via the Cytohesin/GRP-1, Arf, and PIP5K/PPK- 12 / 17 IIS Regulators Cytohesin and PIP5K Modulate Nematode Excitotoxicity 1 complex. It should be noted that ample evidence exists in mammals for a functional interaction between GluRs and insulin signaling. Some of these studies describe a rapid effect of insulin receptors on GluR distribution. Interestingly, a seminal study shows that a phosphatase that degrades PIP3 is associated with the PSD and serves to suppress excitotoxic neurodegeneration, a scenario that is in line with our model. For the time being we do not know if some of the neuroprotective or neurotoxic effects of Glu are mediated by GluRIIS cross talk that regulates neuroprotection by FoxO/DAF-16. Therefore it is not clear if the level of IIS signaling is a “pre-existing condition”that determine susceptibility to neurodegeneration, or if it can be actively modified by Glu signaling, providing an important venue for Glu to control both neurodegeneration and cell survival. Non-enzymatic glycation of proteins is a post-translational modification process, leading to the formation of fructosamine and advanced glycation end products . It has also been reported that there is the generation of oxygen free radicals in the formation of early and advance