Transgenic overexpression of 14-3-3 zeta protects hippocampus against endoplasmic reticulum stress and status epilepticus in vivo

PLoS One. 2013;8(1):e54491. doi: 10.1371/journal.pone.0054491. Epub 2013 Jan 24.

Abstract

14-3-3 proteins are ubiquitous molecular chaperones that are abundantly expressed in the brain where they regulate cell functions including metabolism, the cell cycle and apoptosis. Brain levels of several 14-3-3 isoforms are altered in diseases of the nervous system, including epilepsy. The 14-3-3 zeta (ζ) isoform has been linked to endoplasmic reticulum (ER) function in neurons, with reduced levels provoking ER stress and increasing vulnerability to excitotoxic injury. Here we report that transgenic overexpression of 14-3-3ζ in mice results in selective changes to the unfolded protein response pathway in the hippocampus, including down-regulation of glucose-regulated proteins 78 and 94, activating transcription factors 4 and 6, and Xbp1 splicing. No differences were found between wild-type mice and transgenic mice for levels of other 14-3-3 isoforms or various other 14-3-3 binding proteins. 14-3-3ζ overexpressing mice were potently protected against cell death caused by intracerebroventricular injection of the ER stressor tunicamycin. 14-3-3ζ overexpressing mice were also potently protected against neuronal death caused by prolonged seizures. These studies demonstrate that increased 14-3-3ζ levels protect against ER stress and seizure-damage despite down-regulation of the unfolded protein response. Delivery of 14-3-3ζ may protect against pathologic changes resulting from prolonged or repeated seizures or where injuries provoke ER stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / genetics*
  • Animals
  • Apoptosis
  • Base Sequence
  • Cells, Cultured
  • DNA Primers
  • Endoplasmic Reticulum / metabolism*
  • Hippocampus / cytology
  • Hippocampus / metabolism*
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Real-Time Polymerase Chain Reaction
  • Status Epilepticus / metabolism*

Substances

  • 14-3-3 Proteins
  • DNA Primers

Grant support

This study was funded by Science Foundation Ireland awards 08/IN.1/B1875 and 08/RFP/1745 and by Health Research Board award HRA-POR/2011/41. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.