The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model.
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.
Inoue
Haruhisa
H
Laboratory for Motor System Neurodegeneration, RIKEN Brain Science Institute (BSI), Saitama, PRESTO, Japan.
Tsukita
Kayoko
K
Iwasato
Takuji
T
Suzuki
Yasuyuki
Y
Tomioka
Masanori
M
Tateno
Minako
M
Nagao
Masahiro
M
Kawata
Akihiro
A
Saido
Takaomi C
TC
Miura
Masayuki
M
Misawa
Hidemi
H
Itohara
Shigeyoshi
S
Takahashi
Ryosuke
R
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism*; D017931:DNA Primers; D004195:Disease Models, Animal; D005838:Genotype; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D051636:X-Linked Inhibitor of Apoptosis Protein
D015853:Cysteine Proteinase Inhibitors; D017931:DNA Primers; D011506:Proteins; C000606290:SOD1 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1