Instrumental activation of bid by caspase-1 in a transgenic mouse model of ALS.
Transgenic expression of mutant superoxide dismutase-1 (SOD1) produces an animal model of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. We have previously shown that the mitochondrial-dependent programmed cell death (PCD) pathway, including the redistribution of Bax, the cytosolic release of cytochrome c, and the activation of caspase-9, is recruited during neurodegeneration in spinal cords of transgenic mutant SOD1 mice. Herein, we show that the pro-PCD protein Bid is highly expressed in spinal cords of both wild-type and transgenic mutant SOD1 mice. While full-length Bid is found in the spinal cord of the two groups of mice, its cleaved form is only seen in transgenic mutant SOD1 mice, as early as the beginning of symptoms. In contrast, activated caspase-8, which is known to cleave Bid, is detected only at the end-stage of the disease. We also found that the expression of a dominant negative mutant of caspase-1 attenuates Bid cleavage as well as the mitochondrial release of cytochrome c, and the ensuing activation of caspase-9 and -3 in spinal cords of transgenic mutant SOD1 mice. These findings suggest that Bid cleavage may occur in this model by a pathway other than caspase-8 and shed light onto the molecular correlates of the previously reported beneficial effect of caspase-1 inhibition in transgenic mutant SOD1 mice.
Guégan
Christelle
C
Department of Neurology, Columbia University, New York, New York 10032, USA.
Vila
Miquel
M
Teismann
Peter
P
Chen
Caiping
C
Onténiente
Brigitte
B
Li
Mingwei
M
Friedlander
Robert M
RM
Przedborski
Serge
S
Teissman
Peter
P
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein; D001692:Biological Transport / Q000502:physiology; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009154:Mutation; D012016:Reference Values; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000494:pharmacology; D000072105:Superoxide Dismutase-1
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D003574:Cytochrome c Group; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020170:Caspase 1