The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model

Haruhisa Inoue, Kayoko Tsukita, Takuji Iwasato, Yasuyuki Suzuki, Masanori Tomioka, Minako Tateno, Masahiro Nagao, Akihiro Kawata, Takaomi C. Saido, Masayuki Miura, Hidemi Misawa, Shigeyoshi Itohara, Ryosuke Takahashi

Research output: Contribution to journalArticlepeer-review

98 Citations (Scopus)


Mutant copper/zinc superoxide dismutase (SOD1)-overexpressing transgenic mice, a mouse model for familial amyotrophic lateral sclerosis (ALS), provides an excellent resource for developing novel therapies for ALS. Several observations suggest that mitochondria-dependent apoptotic signaling, including caspase-9 activation, may play an important role in mutant SOD1-related neurodegeneration. To elucidate the role of caspase-9 in ALS, we examined the effects of an inhibitor of X chromosome-linked inhibitor of apoptosis (XIAP), a mammalian inhibitor of caspase-3, -7 and -9, and p35, a baculoviral broad caspase inhibitor that does not inhibit caspase-9. When expressed in spinal motor neurons of mutant SOD1 mice using transgenic techniques, XIAP attenuated disease progression without delaying onset. In contrast, p35 delayed onset without slowing disease progression. Moreover, caspase-9 was activated in spinal motor neurons of human ALS subjects. These data strongly suggest that caspase-9 plays a crucial role in disease progression of ALS and constitutes a promising therapeutic target.

Original languageEnglish
Pages (from-to)6665-6674
Number of pages10
JournalEMBO Journal
Issue number24
Publication statusPublished - 2003 Dec 15
Externally publishedYes


  • ALS
  • Baculovirus p35
  • Caspase
  • SOD1
  • XIAP

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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