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X‐Linked inhibitor of apoptosis protein is involved in mutant SOD1‐mediated neuronal degeneration
Author(s) -
Ishigaki Shinsuke,
Liang Yideng,
Yamamoto Masahiko,
Niwa Junichi,
Ando Yoshio,
Yoshihara Tsuyoshi,
Takeuchi Hideyuki,
Doyu Manabu,
Sobue Gen
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.00998.x
Subject(s) - xiap , sod1 , inhibitor of apoptosis , apoptosis , microbiology and biotechnology , genetically modified mouse , mutant , amyotrophic lateral sclerosis , biology , caspase , programmed cell death , cancer research , chemistry , transgene , gene , medicine , biochemistry , disease
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.