Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice

Ryo Yamasaki, Jian Zhang, Ichiro Koshiishi, Dewi F. Sastradipura Suniarti, Zhou Wu, Christoph Peters, Michael Schwake, Yasuo Uchiyama, Jun ichi Kira, Paul Saftig, Hideo Utsumi, Hiroshi Nakanishi

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26 Citations (Scopus)

Abstract

Nitric oxide (NO) and peroxynitrite, which are produced by activated microglia, are responsible for accelerated neurodegeneration in cathepsin D-deficient (CD-/-) mice. To elucidate the mechanisms by which microglia are initially activated in CD-/- mice, we analyzed the possible relationship between lysosomal storage and microglial activation. In CD-/- mice, the microglial NO-generating activity that was closely associated with the induction of inducible NO synthase and the cationic amino acid transporter-2 (CAT-2) coincided well with the lysosomal storage of subunit c of mitochondrial F0F1ATPase and the formation of ceroid/lipofuscin. Furthermore, activated microglia, which are often accumulating subunit c and ceroid/lipofuscin, showed proliferation activity and an activation of p38 mitogen-activated protein (MAP) kinase. In the primary cultured microglia, pepstatin A was found to enhance the generation of NO and superoxide anion radicals. In these pepstatin A-treated microglia, both an increased generation of the intracellular reactive oxygen species (ROS) and an activation of p38 MAP kinase were observed. These results suggest that the ceroid/lipofuscin which form in microglia activate the p38 MAP kinase cascade through the increased intracellular generation of ROS in CD-/- mice. The activated p38 MAP kinase cascade then promotes the expression of iNOS and CAT-2, thereby inducing the overproduction of NO.

Original languageEnglish
Pages (from-to)573-584
Number of pages12
JournalMolecular and Cellular Neuroscience
Volume35
Issue number4
DOIs
Publication statusPublished - Aug 2007

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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    Yamasaki, R., Zhang, J., Koshiishi, I., Sastradipura Suniarti, D. F., Wu, Z., Peters, C., Schwake, M., Uchiyama, Y., Kira, J. I., Saftig, P., Utsumi, H., & Nakanishi, H. (2007). Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice. Molecular and Cellular Neuroscience, 35(4), 573-584. https://doi.org/10.1016/j.mcn.2007.05.002