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Recruitment of the mitochondrial-dependent apoptotic pathway in amyotrophic lateral sclerosis
C Guégan1, M Vila, G Rosoklija
1Department of Neurology, Columbia University, New York, New York 10032, USA.
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.
Insights
Mutant superoxide dismutase-1 (mSOD1) triggers apoptosis in motor neurons, a key factor in amyotrophic lateral sclerosis (ALS). This study reveals the mitochondrial apoptosis pathway is sequentially activated in mSOD1 mice and ALS patients, suggesting neuroprotective targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Cellular Biology
Background:
- Mutant superoxide dismutase-1 (mSOD1) is the sole known genetic cause of amyotrophic lateral sclerosis (ALS).
- Apoptosis, or programmed cell death, is implicated in motor neuron degeneration observed in ALS.
Purpose of the Study:
- To investigate the role of the mitochondrial-dependent apoptosis pathway in motor neuron degeneration caused by mSOD1.
- To determine if molecular events of apoptosis are sequential in mSOD1-linked ALS.
Main Methods:
- Utilized transgenic mSOD1 mice models of ALS.
- Examined protein translocation (Bax, cytochrome c) and caspase activation (caspase-9, caspase-7) in spinal cord tissues.
- Performed immunohistochemical analysis on spinal cord samples from sporadic ALS patients.
Main Results:
- Observed translocation of Bax to mitochondria and cytochrome c to cytosol in mSOD1 mouse spinal cords during disease progression.
- Detected activation of caspase-9 in mSOD1 mouse spinal cords.
- Found downstream caspase-7 activation and XIAP cleavage only in end-stage mSOD1 mice.
- Confirmed cytochrome c translocation in spinal cords of sporadic ALS patients.
Conclusions:
- The mitochondrial-dependent apoptotic pathway is sequentially activated in the context of mSOD1-related motor neuron degeneration.
- Cytochrome c translocation, a key apoptotic event, occurs in both transgenic mSOD1 mice and human sporadic ALS.
- Targeting molecules within this apoptotic cascade may offer neuroprotective strategies for ALS treatment.