title: Dysequilibrium between caspases and their inhibitors in a mouse model for amyotrophic lateral sclerosis.
abstract: Mutations in copper/zinc superoxide dismutase (SOD1) have been implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 protein likely gains a novel cytotoxic property, leading to the death of motor neurons. We therefore investigated whether caspase-mediated apoptosis is associated with novel cytotoxic properties in a rodent model for familial ALS (G93A SOD1 transgenic mice). Caspase-9 (an effecter in the mitochondrial apoptotic pathway), caspase-8 (an effecter in the Fas apoptotic pathway), and caspase-3 (an executioner of both pathways) proteins were all present in nonactive forms in the spinal cords of wild-type mice during the early stage of the disease (8 weeks), at which time the mice had not yet exhibited motor paralysis. In transgenic mice, however, these proteins were present in their active forms, and their mRNA levels were significantly upregulated in the represent to this conversion from nonactive to active forms. During the advanced stage of the disease (16 weeks), when paralysis was evident, the active caspase levels were further elevated. On the other hand, the mRNA and protein levels of survivin, a counteraction protein against caspases, were significantly suppressed during the early stage, and sharply increased during the advanced stage. Although the mRNA and protein levels of X-linked inhibitor of apoptosis protein (XIAP) remained at the same levels as those seen in the control (wild-type mice) during the early stage, they were significantly depressed at an age of 16 weeks. These findings were observed exclusively in the spinal cord, the region responsible for the disease, and not in the cerebellum, a non-responsible region. We conclude that conditions facilitating the apoptotic process during the early stage of the disease play causative roles in the pathogenesis of ALS and that the suppression of XIAP levels during the advanced stage could contribute to disease expression and/or progression.
authors.affiliation: Research Unit of Clinical Pharmacy, College of Pharmacy, Nihon University, 7-7-1, Narashinodai, Funabashi, Chiba, 274-8555, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tokuda
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Ono
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ishige
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Watanabe
authors.forename: Eriko
authors.initials: E
authors.lastname: Okawa
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Ito
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002490:Central Nervous System / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D018384:Oxidative Stress / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D000077022:Survivin; D015854:Up-Regulation / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020169:Caspases