Depletion of 14-3-3 zeta elicits endoplasmic reticulum stress and cell death, and increases vulnerability to kainate-induced injury in mouse hippocampal cultures.

Abstract

14-3-3 proteins are ubiquitous signalling molecules that regulate development and survival pathways in brain. Altered expression and cellular localization of 14-3-3 proteins has been implicated in neurodegenerative diseases and in neuronal death after acute neurological insults, including seizures. Presently, we examined expression and function of 14-3-3 isoforms in vitro using mouse organotypic hippocampal cultures. Treatment of cultures with the endoplasmic reticulum (ER) stressor tunicamycin caused an increase in levels of 14-3-3 zeta within the ER-containing microsomal fraction, along with up-regulation of Lys-Asp-Glu-Leu-containing proteins and calnexin, and the selective death of dentate granule cells. Depletion of 14-3-3 zeta levels using small interfering RNA induced both ER stress proteins and death of granule cells. Treatment of hippocampal cultures with the excitotoxin kainic acid increased levels of Lys-Asp-Glu-Leu-containing proteins and microsomal 14-3-3 zeta levels and caused cell death within the CA1, CA3 and dentate gyrus of the hippocampus. Kainic acid-induced damage was significantly increased in each hippocampal subfield of cultures treated with small interfering RNA targeting 14-3-3 zeta. The present data indicate a role for 14-3-3 zeta in survival responses following ER stress and possibly protection against seizure injury to the hippocampus.

• Authors: Niamh Murphy, Helena P Bonner, Manus W Ward, Brona M Murphy, Jochen H M Prehn, David C Henshall
• Journal: Journal of neurochemistry (J Neurochem) Vol. 106 Issue 2 Pg. 978-88 (Jul 2008) ISSN: 1471-4159 [Electronic] England
• PMID: 18466333 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 14-3-3 Proteins
• Excitatory Amino Acid Agonists
• Oligopeptides
• Protein Sorting Signals
• RNA, Small Interfering
• Tunicamycin
• lysyl-aspartyl-glutamyl-leucine
• Calnexin
• Veratridine
• Kainic Acid

Topics

• 14-3-3 Proteins (metabolism)
• Analysis of Variance
• Animals
• Calnexin (metabolism)
• Cell Death (drug effects)
• Endoplasmic Reticulum (drug effects)
• Excitatory Amino Acid Agonists (toxicity)
• Hippocampus (cytology, drug effects)
• Kainic Acid (toxicity)
• Mice
• Neurons (drug effects, ultrastructure)
• Oligopeptides (metabolism)
• Organ Culture Techniques
• Protein Sorting Signals
• RNA, Small Interfering (pharmacology)
• Subcellular Fractions (drug effects, metabolism)
• Tunicamycin (pharmacology)
• Up-Regulation (drug effects)
• Veratridine (pharmacology)