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

研究成果: Contribution to journalArticle査読

26 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)573-584
ページ数12
ジャーナルMolecular and Cellular Neuroscience
35
4
DOI
出版ステータス出版済み - 8 2007

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 細胞および分子神経科学
  • 細胞生物学

フィンガープリント

「Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル