title: The insulin/IGF signaling regulators cytohesin/GRP-1 and PIP5K/PPK-1 modulate susceptibility to excitotoxicity in C. elegans.
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.
authors.affiliation: Physiology Pharmicology & Neuroscience, Sophie Davis School of Biomedical Education, City College of New York (CCNY), The City University of New York (CUNY), New York, New York, United States of America; Graduate Program in Neurobiology, The Graduate Center, The City University of New York (CUNY), New York, New York, United States of America.
authors.forename: Nazila
authors.initials: N
authors.lastname: Tehrani
authors.affiliation: Physiology Pharmicology & Neuroscience, Sophie Davis School of Biomedical Education, City College of New York (CCNY), The City University of New York (CUNY), New York, New York, United States of America; MA Program in Biology, City College of New York (CCNY), The City University of New York (CUNY), New York, New York, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Del Rosario
authors.affiliation: Physiology Pharmicology & Neuroscience, Sophie Davis School of Biomedical Education, City College of New York (CCNY), The City University of New York (CUNY), New York, New York, United States of America; Undergraduate Program in Biology, City College of New York (CCNY), The City University of New York (CUNY), New York, New York, United States of America.
authors.forename: Moises
authors.initials: M
authors.lastname: Dominguez
authors.affiliation: Neuroscience Graduate Group, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Kalb
authors.affiliation: Physiology Pharmicology & Neuroscience, Sophie Davis School of Biomedical Education, City College of New York (CCNY), The City University of New York (CUNY), New York, New York, United States of America; Graduate Program in Neurobiology, The Graduate Center, The City University of New York (CUNY), New York, New York, United States of America.
authors.forename: Itzhak
authors.initials: I
authors.lastname: Mano
mesh_terms: D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D009336:Necrosis / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D013002:Somatomedins; D014157:Transcription Factors; C579560:Zfp-1 protein, C elegans; C100723:cytohesin-1; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C531146:Ppk-1 protein, C elegans; C100662:AGE-1 protein, C elegans