XIAP decreases caspase-12 cleavage and calpain activity in spinal cord of ALS transgenic mice.
Amyotrophic lateral sclerosis (ALS) is characterized by the selective degeneration of motor neurons. The cause for nerve cell demise is not clear but involves activation of the caspase family of cysteine proteases. We have shown that ER stress and caspase-12 activation occur in ALS transgenic mice carrying the mutant copper/zinc superoxide dismutase (SOD1) gene. In these mice, we found that the antiapoptotic proteins, X-linked Inhibitor of Apoptosis Protein (XIAP) and the related protein, MIAP2 were decreased. To study the role of this, we generated double transgenic mice expressing XIAP in ALS spinal cord neurons using the Thy1 promoter. Overexpression of XIAP inhibited caspase-12 cleavage and reduced calpain activity in the ALS mice. XIAP also reduced the breakdown of calpastatin that is an inhibitor of calpain. In the double transgenic mice, life span was increased by about 12%. These data support the view that XIAP has beneficial effects in ALS and extends survival. The neuroprotective effect of XIAP involves inhibition of caspases and the stabilization of the calpastatin/calpain system that is altered in the ALS mice.
Department of Neuroscience, Unit of Neurobiology, Uppsala University, Biomedical Centre, Box 587, S-751 23 Uppsala, Sweden.
Hanna
H
Wootz
Inga
I
Hansson
Laura
L
Korhonen
Dan
D
Lindholm
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D053454:Caspase 12; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015996:Survival Rate; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; C000606290:SOD1 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C033668:calpastatin; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; C506444:CASP12 protein, human; D002154:Calpain; C506440:Casp12 protein, mouse; D053454:Caspase 12; D020169:Caspases