Amyotrophic lateral sclerosis (ALS) is a progressive age-dependent disease involving degeneration of motor neurons in the brain, brainstem and spinal cord. ALS is universally fatal, with the median survival of patients being five years from diagnosis. In a transgenic mouse model of ALS, we now show that a dominant negative inhibitor of a cell-death gene, the interleukin-1β-converting enzyme (ICE), significantly slows the symptomatic progression of ALS.
ALS exists in both sporadic and familial forms. Certain familial forms are caused by mutations in the Cu/Zn superoxide dismutase (SOD-1) gene1. Transgenic mice expressing mutant SOD-1 genes develop an age-dependent progressive motor weakness similar to human ALS2. Although little is known about the mechanism of cell death in ALS, downregulation of SOD-1 activity using antisense SOD-1 DNA in vitro has been shown to promote apoptosis in a neuronal cell line3. Cell death in this model was mediated in part by the activation of ICE and by binding of endogenously produced mature interleukin-1β (IL-1β) to its receptor4.
We have previously shown that endogenous mature IL-1β, produced by activation of ICE, is important in a variety of cell-death models5. We recently reported a transgenic mouse expressing a dominant negative inhibitor of ICE, which has the active-site cysteine substituted for a glycine, in neurons under the control of a neuronal specific enolase promoter (NSE-M17Z)6. Developmental neuronal cell death does not seem to be inhibited in these transgenic mice, as the brain is of normal size, they exhibit normal behaviour, and have equivalent numbers of neurons in the facial motor nucleus as the wild-type control mice6. This contrasts with the NSE-Bcl-2 transgenic mice which have larger brains and more neurons7.
To determine whether inhibition of ICE activity in vivo might halt the progression of the ALS-like syndrome in mice expressing mutant SOD-1, we crossed five female NSE-M17Z mice from one transgenic founder mouse with one mutant SOD(G93R) male mouse. We determined the genotypes of the progeny from these crosses using the polymerase chain reaction (PCR) to find carriers of the mutant ICE and SOD transgenes, and monitored littermates of SOD(G93R) mice and those with both SOD(G93R) and mutant ICE for the times of disease onset and death. The onset of the disease was scored as the date of the first observation of significantly slower gait and/or limb paralysis. Mortality was scored as the date of death or the inability of the mouse to right itself in 30 s (scorers were unaware of the genotypes of the mice or their birth dates).
Although the timing of disease onset in the mutant SOD and mutant SOD/ mutant ICE (M17Z) transgenic mice is not different, the double-transgenic mice survive significantly longer from the onset of the disease (27 days) than the mutant SOD mice (11.7 days) (Table 1). Therefore, expression of the dominant negative inhibitor of ICE in neurons of mutant SOD mice is able to slow the symptomatic progression of this disease and delay mortality. Our results indicate that ICE-like proteases might affect disease progression in this ALS mouse model and suggest that ICE inhibitors may be of value in the treatment of ALS in humans.
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Friedlander, R., Brown, R., Gagliardini, V. et al. Inhibition of ICE slows ALS in mice. Nature 388, 31 (1997). https://doi.org/10.1038/40299
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