Abnormal production of macrophage inflammatory protein-1alpha by microglial cell lines derived from neonatal brains of Sandhoff disease model mice.

Abstract

Sandhoff disease (SD) is a lysosomal beta-hexosaminidase deficiency involving excessive accumulation of undegraded substrates, including terminal N-acetylglucosamine-oligosaccharides and GM2 ganglioside, and progressive neurodegeneration. Our previous study demonstrated remarkable induction of macrophage inflammatory factor-1alpha (MIP-1alpha) in microglia in the brains of SD model mice as a putative pathogenic factor for SD via microglia-mediated neuroinflammation. In this study, we established microglial cell lines (WT- and SD-Mg) from wild-type and SD mice, and first demonstrated the enhanced production of MIP-1alpha in SD-Mg. Inhibitors of protein kinase C (PKC) and Akt reduced the production of MIP-1alpha by SD-Mg. Elevated activation of Akt and partial translocation of PKC isozymes (alpha, betaI, betaII, and delta) from the cytoplasm to the membrane in SD-Mg were also revealed by means of immunoblotting. Furthermore, it was demonstrated that intracellular extracellular signal-regulated kinase, c-Jun N-terminal kinase, and phospholipase C (PLC), but not phosphoinositide 3-kinase, should contribute to the induction of MIP-1alpha in SD-Mg, and that PLC could independently regulate the activation of both PKC and Akt. We proposed here that the deregulated activation of PLC should cause the enhanced MIP-1alpha production via plural signaling pathways mediated by PKC and Akt, followed by extracellular signal-regulated kinase and c-Jun N-terminal kinase, in SD-Mg.

• Authors: Eri Kawashita, Daisuke Tsuji, Nagako Kawashima, Ken-ichi Nakayama, Hiroyuki Matsuno, Kohji Itoh
• Journal: Journal of neurochemistry (J Neurochem) Vol. 109 Issue 5 Pg. 1215-24 (Jun 2009) ISSN: 1471-4159 [Electronic] England
• PMID: 19302485 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ccl3 protein, mouse
• Chemokine CCL3
• Enzyme Inhibitors
• RNA, Messenger
• Oncogene Protein v-akt
• Protein Kinase C
• Mitogen-Activated Protein Kinase 3
• beta-Hexosaminidase beta Chain

Topics

• Animals
• Animals, Newborn
• Brain (pathology)
• Cells, Cultured
• Chemokine CCL3 (genetics, metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation (drug effects)
• Mice
• Mice, Knockout
• Microglia (drug effects, metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Oncogene Protein v-akt (metabolism)
• Protein Kinase C (metabolism)
• Protein Transport (drug effects)
• RNA, Messenger (metabolism)
• Sandhoff Disease (pathology)
• Signal Transduction (drug effects, physiology)
• Subcellular Fractions (drug effects, metabolism)
• beta-Hexosaminidase beta Chain (genetics)