Inhibiting cell death proteases, or caspases, can prolong the life of mice with the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), Robert Friedlander of Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, report in the April 14 Science. Friedlander and colleagues provide evidence that caspases play a functional role throughout the disease, starting even before symptoms appear. The study continues work published since 1997 that reported similar results-early activation of caspases and partial treatment success by inhibiting them-for mouse models of stroke, Huntington’s disease, and traumatic brain damage. Data on spinal cord injury are in press. Friedlander and colleagues infused a broad, tripeptide caspase inhibitor into the cerebral ventricle of transgenic mice expressing mutant SOD1. These widely used mice develop symptoms around 90 days of age and die roughly 35 days later. Treated mice showed symptoms 20 days later and lived an average of 26 days longer. Mark Gurney of Pharmacia Corporation, who first developed the mouse model, points out in an accompanying Perspectives article that this effect doubles that of riluzole, the only FDA-approved treatment.
The approach is controversial because apoptosis is sometimes thought to occur at the end stage of neurodegenerative diseases, raising the question whether interfering with it will benefit a patient. Yet Friedlander says, “To me, caspases do not equal cell death. They equal making a cell sick, slowly worsening its dysfunction, and eventually death.” Of the 14 caspases found so far, some act early in the cell death pathway, he adds. This study found caspase-1 and caspase-3 were cleaved into their active state 20 days prior to the first clinical symptoms.
Moreover, Friedlander suggests that apoptosis is “contagious.” In chronic neurodegenerative diseases, all neurons do not die simultaneously. Those that have progressed farther through the highly regulated caspase pathway release diffusible factors including the caspase-1 product IL-1β, which accelerate the deterioration of still-functional neurons nearby. In support of this notion, he reports a 2.4-fold increase in mature IL-1β levels in the spinal cords of sick, untreated mice, which the drug reduced by 37 percent. This reduction in turn decreased further gene expression of caspase-1 and 3. The study also shows an 87% elevation of IL-1β levels in spinal cord samples of ALS patients.—Gabrielle Strobel
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- Li M, Ona VO, Guégan C, Chen M, Jackson-Lewis V, Andrews LJ, Olszewski AJ, Stieg PE, Lee JP, Przedborski S, Friedlander RM. Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science. 2000 Apr 14;288(5464):335-9. PubMed.