Calpain mediates excitotoxic DNA fragmentation via mitochondrial pathways in adult brains: Evidence from calpastatin mutant mice

Jiro Takano, Masanori Tomioka, Satoshi Tsubuki, Makoto Higuchi, Nobuhisa Iwata, Shigeyoshi Itohara, Masatoshi Maki, Takaomi C. Saido

研究成果: ジャーナルへの寄稿学術論文査読

180 被引用数 (Scopus)

抄録

Calpain has been implicated in excitotoxic neurodegeneration, but its mechanism of action particularly in adult brains remains unclear. We generated mutant mice lacking or overexpressing calpastatin, the only solely calpain-specific inhibitor ever identified or synthesized. Modulation of calpastatin expression caused no defect in the mice under normal conditions, indicating that calpastatin functions as a negative regulator of calpain only under pathological conditions. Kainate-evoked excitotoxicity in hippocampus resulted in proteolytic activation of a proapoptotic Bcl-2 subfamily member (Bid), nuclear translocation of mitochondria-derived DNA fragmentation factors (apoptosis-inducing factor and endonuclease G), DNA fragmentation, and nuclear condensation in pyramidal neurons. These apoptotic responses were significantly augmented by calpastatin deficiency. Consistently calpastatin overexpression suppressed them. No evidence of caspase-3 activation was detected. Our results demonstrated that calpain mediates excitotoxic signals through mobilization of proapoptotic factors in a caspase-independent manner. These mutant mice will serve as useful tools for investigating calpain involvement in various diseases.

本文言語英語
ページ(範囲)16175-16184
ページ数10
ジャーナルJournal of Biological Chemistry
280
16
DOI
出版ステータス出版済み - 22-04-2005
外部発表はい

All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子生物学
  • 細胞生物学

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