Recruitment of the mitochondrial-dependent apoptotic pathway in amyotrophic lateral sclerosis.
Molecular mechanisms of apoptosis may participate in motor neuron degeneration produced by mutant superoxide dismutase-1 (mSOD1), the only proven cause of amyotrophic lateral sclerosis (ALS). Consistent with this, here we show that the proapoptotic protein Bax translocates from the cytosol to the mitochondria, whereas cytochrome c translocates from the mitochondria to the cytosol in spinal cords of transgenic mSOD1 mice during the progression of the disease. Concomitantly, caspase-9 is activated in the spinal cord of transgenic mSOD1 mice. Only in end-stage transgenic mSOD1 mice is the downstream caspase-7 activated and the inhibitor of apoptosis, XIAP, cleaved. These results indicate a sequential recruitment of molecular elements of the mitochondrial-dependent apoptotic pathway in transgenic mSOD1 mice. We also provide immunohistochemical evidence that cytochrome c translocation occurs in the spinal cord of sporadic ALS patients. Collectively, these data suggest that the mitochondrial-dependent apoptotic pathway may contribute to the demise of motor neurons in ALS and that targeting key molecules of this cascade may prove to be neuroprotective.
Guégan
C
C
Department of Neurology, Columbia University, New York, New York 10032, USA.
Vila
M
M
Rosoklija
G
G
Hays
A P
AP
Przedborski
S
S
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D051636:X-Linked Inhibitor of Apoptosis Protein; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; D003574:Cytochrome c Group; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C000606290:SOD1 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051028:bcl-2-Associated X Protein; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C505520:CASP7 protein, human; C506433:CASP9 protein, human; C505524:Casp7 protein, mouse; C506434:Casp9 protein, mouse; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases