Overexpression of the PDZ1 domain of PSD-95 diminishes ischemic brain injury via inhibition of the GluR6.PSD-95.MLK3 pathway.

Abstract

Recent studies have shown that kainate (KA) receptors are involved in neuronal cell death induced by seizure, which is mediated by the GluR6.PSD-95.MLK3 signaling module and subsequent JNK activation. In our previous studies, we demonstrated the neuroprotective role of a GluR6 c-terminus containing peptide against KA or cerebral ischemia-induced excitotoxicity in vitro and in vivo. Here, we first report that overexpression of the PDZ1 domain of PSD-95 protein exerts a protective role against neuronal death induced by cerebral ischemia-reperfusion in vivo and can prevent neuronal cell death induced by oxygen-glucose deprivation. Further studies show that overexpression of PDZ1 can perturb the interaction of GluR6 with PSD-95 and suppress the assembly of the GluR6.PSD-95.MLK3 signaling module and therefore inhibit JNK activation. Thus, it not only inhibits phosphorylation of c-Jun and down-regulates Fas ligand expression but also inhibits phosphorylation of 14-3-3 and decreases Bax translocation to mitochondria, decreases the release of cytochrome c, and decreases caspase-3 activation. Overall, the essential role of the PDZ1 domain of PSD-95 in apoptotic cell death in neurons provides an experimental foundation for gene therapy of neurodegenerative diseases with overexpression of the PDZ1 domain.

• Authors: Shu-Qun Hu, Jie Zhu, Dong-Sheng Pei, Yan-Yan Zong, Jing-Zhi Yan, Xiao-Yu Hou, Guang-Yi Zhang
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 87 Issue 16 Pg. 3626-38 (Dec 2009) ISSN: 1097-4547 [Electronic] United States
• PMID: 19610093 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2009 Wiley-Liss, Inc.

Chemical References

• DLG4 protein, human
• Disks Large Homolog 4 Protein
• Gluk2 kainate receptor
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Receptors, Kainic Acid
• bcl-2-Associated X Protein
• Cytochromes c
• JNK Mitogen-Activated Protein Kinases
• Glucose

Topics

• Analysis of Variance
• Animals
• Blotting, Western
• Cell Death (genetics)
• Cell Fractionation
• Cell Line
• Cells, Cultured
• Cytochromes c (metabolism)
• Disks Large Homolog 4 Protein
• Glucose (deficiency)
• Hippocampus (metabolism, pathology)
• Humans
• Hypoxia (genetics, metabolism)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Male
• Membrane Proteins (genetics, metabolism)
• Mitochondria (genetics, metabolism)
• Neurons (metabolism, pathology)
• Phosphorylation (genetics)
• Protein Transport (genetics)
• Rats
• Rats, Sprague-Dawley
• Receptors, Kainic Acid (metabolism)
• Reperfusion Injury (genetics, metabolism, pathology)
• Signal Transduction (physiology)
• Subcellular Fractions (metabolism, pathology)
• bcl-2-Associated X Protein (genetics, metabolism)