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The Journal of Neuroscience, September 1, 2001, 21(17):6569-6576
Recruitment of the Mitochondrial-Dependent Apoptotic Pathway in Amyotrophic Lateral Sclerosis
Christelle Guégan1, Miquel Vila1, Gorazd Rosoklija2, Arthur P. Hays2, and Serge Przedborski1, 2 Departments of 1 Neurology and 2 Pathology, Columbia University, New York, New York 10032
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.
Key words: amyotrophic lateral sclerosis; apoptosis; Bax; caspase; cytochrome c; mitochondria; superoxide dismutase; neurodegeneration
Copyright © 2001 Society for Neuroscience 0270-6474/01/21176569-08$05.00/0
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