Related Experiment Video
Updated: Jul 22, 2026
Caspase-3 Activity in the Rat Amygdala Measured by Spectrofluorometry After Myocardial Infarction
Published on: January 12, 2016
Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model
1Neuroapoptosis Laboratory and Neurosurgical Service, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Mutations in the copper/zinc superoxide dismutase (SOD1) gene produce an animal model of familial amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. To test a new therapeutic strategy for ALS, we examined the effect of caspase inhibition in transgenic mice expressing mutant human SOD1 with a substitution of glycine to alanine in position 93 (mSOD1(G93A)). Intracerebroventricular administration of zVAD-fmk, a broad caspase inhibitor, delays disease onset and mortality. Moreover, zVAD-fmk inhibits caspase-1 activity as well as caspase-1 and caspase-3 mRNA up-regulation, providing evidence for a non-cell-autonomous pathway regulating caspase expression. Caspases play an instrumental role in neurodegeneration in transgenic mSOD1(G93A) mice, which suggests that caspase inhibition may have a protective role in ALS.
Insights
Inhibiting caspases, enzymes involved in cell death, shows promise for treating familial amyotrophic lateral sclerosis (ALS). This study found caspase inhibition delays disease progression in a mouse model of ALS.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Familial amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease.
- Mutations in the copper/zinc superoxide dismutase (SOD1) gene cause an animal model of familial ALS.
- Caspases are key enzymes implicated in neurodegenerative processes.
Purpose of the Study:
- To investigate the therapeutic potential of caspase inhibition in a mouse model of familial ALS.
- To examine the effects of a broad caspase inhibitor on disease onset and mortality in mSOD1(G93A) mice.
Main Methods:
- Transgenic mice expressing mutant human SOD1 (mSOD1(G93A)) were used.
- Intracerebroventricular administration of the broad caspase inhibitor zVAD-fmk was performed.
- Caspase-1 activity and mRNA levels of caspase-1 and caspase-3 were measured.
Main Results:
- Administration of zVAD-fmk significantly delayed disease onset and mortality in mSOD1(G93A) mice.
- zVAD-fmk inhibited caspase-1 activity.
- zVAD-fmk reduced the up-regulation of caspase-1 and caspase-3 mRNA, suggesting a non-cell-autonomous pathway.
Conclusions:
- Caspases play a critical role in neurodegeneration in the mSOD1(G93A) mouse model of ALS.
- Caspase inhibition demonstrates a protective effect and represents a potential therapeutic strategy for ALS.
- The findings suggest a non-cell-autonomous pathway regulating caspase expression in ALS pathogenesis.
