期刊
JOURNAL OF NEUROSCIENCE
卷 21, 期 17, 页码 6569-6576出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.21-17-06569.2001
关键词
amyotrophic lateral sclerosis; apoptosis; Bax; caspase; cytochrome c; mitochondria; superoxide dismutase; neurodegeneration
资金
- NINDS NIH HHS [P50 NS38370, R01 NS38586, R29 NS37345] Funding Source: Medline
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.
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