title: X-Linked inhibitor of apoptosis protein is involved in mutant SOD1-mediated neuronal degeneration.
abstract: Mutations in the superoxide dismutase 1 (SOD1) gene cause the degeneration of motor neurons in familial amyotrophic lateral sclerosis (FALS). An apoptotic process including caspase-1 and -3 has been shown to participate in the pathogenesis of FALS transgenic (Tg) mouse model. Here we report that IAP proteins, potent inhibitors of apoptosis, are involved in the FALS Tg mouse pathologic process. The levels of X-linked inhibitor of apoptosis protein (XIAP) mRNA and protein were significantly decreased in the spinal cord of symptomatic G93A-SOD1 Tg mice compared with littermates. In contrast, the levels of cIAP-1 mRNA and protein were increased in symptomatic G93A-SOD1 Tg mice, whereas the levels of cIAP-2 mRNA and protein were unchanged. In situ hybridization showed that the expression of XIAP was remarkably reduced in the motor neurons of Tg mice, and the expression of cIAP-1 was strongly increased in the reactive astrocytes of Tg mice. Overexpression of XIAP markedly inhibited the cell death and caspase-3 activity in the neuro2a cells expressing mutant SOD1. Deletional mutant analysis revealed that the N-terminal domain of XIAP, the BIR1-2 domains, was essential for this inhibitory activity. These results suggest that XIAP plays a role in the apoptotic mechanism in the progression of disease in mutant SOD1 Tg mice and holds therapeutic possibilities for FALS.
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ishigaki
authors.forename: Yideng
authors.initials: Y
authors.lastname: Liang
authors.forename: Masahiko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Niwa
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ando
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yoshihara
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Manabu
authors.initials: M
authors.lastname: Doyu
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D011506:Proteins; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase