The insulin/IGF signaling regulators cytohesin/GRP-1 and PIP5K/PPK-1 modulate susceptibility to excitotoxicity in C. elegans

Nazila Tehrani*, John Del Rosario, Moises Dominguez, Robert Kalb, Itzhak Mano

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Article numbere113060
JournalPloS one
Volume9
Issue number11
DOIs
StatePublished - Nov 25 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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