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PMID: 14657037 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The EMBO journal ·Vol. 22 ·No. 24 ·2003-12-15 ·Pages 6665-74

Inoue H, Tsukita K, Iwasato T, Suzuki Y, Tomioka M, Tateno M, Nagao M, Kawata A, Saido TC, Miura M, Misawa H, Itohara S, Takahashi R

Abstract

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.

MeSH Terms
Amyotrophic Lateral Sclerosis/genetics Animals Base Sequence Cysteine Proteinase Inhibitors/metabolism DNA Primers Disease Models, Animal Genotype Immunohistochemistry Mice Mice, Inbred C57BL Mice, Transgenic Proteins/genetics,metabolism Reverse Transcriptase Polymerase Chain Reaction Spinal Cord/enzymology,pathology Superoxide Dismutase/genetics Superoxide Dismutase-1 X-Linked Inhibitor of Apoptosis Protein
Chemicals
Cysteine Proteinase Inhibitors DNA Primers Proteins SOD1 protein, human X-Linked Inhibitor of Apoptosis Protein Sod1 protein, mouse Superoxide Dismutase Superoxide Dismutase-1
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Inoue Haruhisa
Laboratory for Motor System Neurodegeneration, RIKEN Brain Science Institute (BSI), Saitama, PRESTO, Japan.
Tsukita Kayoko
Iwasato Takuji
Suzuki Yasuyuki
Tomioka Masanori
Tateno Minako
Nagao Masahiro
Kawata Akihiro
Saido Takaomi C
Miura Masayuki
Misawa Hidemi
Itohara Shigeyoshi
Takahashi Ryosuke
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdg634
Published
2003-12-15
Pages
6665-74
Language
English
Region
England
NLM ID
8208664
PMCID
PMC291829
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/cdg634 PMC Full Text View journal details
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