Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amyotrophic Lateral Sclerosis / genetics
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Amyotrophic Lateral Sclerosis / metabolism*
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Amyotrophic Lateral Sclerosis / pathology
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Animals
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Apoptosis*
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Blotting, Western
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Caspase 7
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Caspase 9
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Caspases / metabolism
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Cytochrome c Group / metabolism
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Cytosol / metabolism
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Disease Models, Animal
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Enzyme Activation / genetics
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Humans
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Immunohistochemistry
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Mice
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Mice, Transgenic
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Mitochondria / metabolism*
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Protein Transport
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Proteins / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2*
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Spinal Cord / metabolism
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Spinal Cord / pathology
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
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Superoxide Dismutase-1
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X-Linked Inhibitor of Apoptosis Protein
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bcl-2-Associated X Protein
Substances
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BAX protein, human
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Bax protein, mouse
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Cytochrome c Group
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Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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SOD1 protein, human
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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bcl-2-Associated X Protein
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1
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CASP7 protein, human
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CASP9 protein, human
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Casp7 protein, mouse
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Casp9 protein, mouse
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Caspase 7
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Caspase 9
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Caspases