X‐Linked inhibitor of apoptosis protein is involved in mutant SOD1‐mediated neuronal degeneration
Open Access
- 24 July 2002
- journal article
- research article
- Published by Wiley in Journal of Neurochemistry
- Vol. 82 (3), 576-584
- https://doi.org/10.1046/j.1471-4159.2002.00998.x
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.Keywords
This publication has 34 references indexed in Scilit:
- Effect of overexpression of wild‐type and mutant Cu/Zn‐superoxide dismutases on oxidative stress and cell death induced by hydrogen peroxide, 4‐hydroxynonenal or serum deprivation: potentiation of injury by ALS‐related mutant superoxide dismutases and protection by Bcl‐2Journal of Neurochemistry, 2001
- Characterization of XIAP-Deficient MiceMolecular and Cellular Biology, 2001
- Gene expression profile in Alzheimer’s brain screened by molecular indexingMolecular Brain Research, 2001
- Two Novel Genes, Human neugrin and Mouse m-neugrin, Are Upregulated with Neuronal Differentiation in Neuroblastoma CellsBiochemical and Biophysical Research Communications, 2000
- Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspasesThe EMBO Journal, 1999
- IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspasesThe EMBO Journal, 1998
- Bcl-2: Prolonging Life in a Transgenic Mouse Model of Familial Amyotrophic Lateral SclerosisScience, 1997
- X-linked IAP is a direct inhibitor of cell-death proteasesNature, 1997
- ALS-Linked SOD1 Mutant G85R Mediates Damage to Astrocytes and Promotes Rapidly Progressive Disease with SOD1-Containing InclusionsNeuron, 1997
- Motor Neuron Degeneration in Mice that Express a Human Cu,Zn Superoxide Dismutase MutationScience, 1994