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Updated: Aug 11, 2026
Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)
Published on: March 17, 2012
Instrumental activation of bid by caspase-1 in a transgenic mouse model of ALS
Christelle Guégan1, Miquel Vila, Peter Teismann
1Department of Neurology, Columbia University, New York, New York 10032, USA.
Abstract:
Transgenic expression of mutant superoxide dismutase-1 (SOD1) produces an animal model of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. We have previously shown that the mitochondrial-dependent programmed cell death (PCD) pathway, including the redistribution of Bax, the cytosolic release of cytochrome c, and the activation of caspase-9, is recruited during neurodegeneration in spinal cords of transgenic mutant SOD1 mice. Herein, we show that the pro-PCD protein Bid is highly expressed in spinal cords of both wild-type and transgenic mutant SOD1 mice. While full-length Bid is found in the spinal cord of the two groups of mice, its cleaved form is only seen in transgenic mutant SOD1 mice, as early as the beginning of symptoms. In contrast, activated caspase-8, which is known to cleave Bid, is detected only at the end-stage of the disease. We also found that the expression of a dominant negative mutant of caspase-1 attenuates Bid cleavage as well as the mitochondrial release of cytochrome c, and the ensuing activation of caspase-9 and -3 in spinal cords of transgenic mutant SOD1 mice. These findings suggest that Bid cleavage may occur in this model by a pathway other than caspase-8 and shed light onto the molecular correlates of the previously reported beneficial effect of caspase-1 inhibition in transgenic mutant SOD1 mice.
Insights
Bid cleavage occurs in the spinal cords of mice modeling amyotrophic lateral sclerosis (ALS) through a caspase-8-independent pathway. Caspase-1 inhibition prevents this cleavage, offering insights into ALS neurodegeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Death Pathways
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder.
- Transgenic mutant superoxide dismutase-1 (SOD1) expression models ALS.
- Mitochondrial-dependent programmed cell death (PCD) is implicated in ALS neurodegeneration.
Purpose of the Study:
- To investigate the role of the pro-PCD protein Bid in the spinal cords of transgenic mutant SOD1 mice.
- To elucidate the molecular mechanisms of Bid cleavage in ALS.
- To explore the involvement of caspases in Bid-mediated PCD in ALS.
Main Methods:
- Analysis of Bid protein expression and cleavage in wild-type and transgenic mutant SOD1 mice.
- Detection of activated caspase-8 and caspase-1.
- Assessment of mitochondrial cytochrome c release and caspase activation (caspase-9, -3) following caspase-1 inhibition.
Main Results:
- Full-length Bid is present in both wild-type and mutant SOD1 mice, but cleaved Bid is detected only in mutant SOD1 mice.
- Cleaved Bid appears early in symptom onset, preceding the detection of activated caspase-8.
- Inhibition of caspase-1 attenuates Bid cleavage, cytochrome c release, and subsequent caspase activation in mutant SOD1 mice.
Conclusions:
- Bid cleavage in this ALS model likely occurs via a caspase-8-independent pathway.
- Caspase-1 plays a significant role in mediating Bid cleavage and downstream PCD events in ALS.
- These findings provide molecular insights into the therapeutic benefits of caspase-1 inhibition in ALS.
