Dissociation between neurodegeneration and caspase-11-mediated activation of caspase-1 and caspase-3 in a mouse model of amyotrophic lateral sclerosis.
Caspase-11 is a key regulator of caspase-1 and caspase-3 activation under pathological conditions. We show here that the expression of caspase-11 is upregulated in the spinal cord of superoxide dismutase 1 (SOD1) G93A transgenic mice, a mouse model of amyotrophic lateral sclerosis (ALS), before the onset of motor dysfunction and remains at the high levels throughout the course of disease. The caspase-1- and caspase-3-like activities, as well as the level of interleukin-1beta, were significantly reduced in the spinal cord of symptomatic caspase-11-/-;SOD1 G93A mice compared with that of caspase-11+/-; SOD1 G93A mice. However, neurodegeneration, inflammatory responses, and the disease onset and progression in SOD1 G93A transgenic mice were not altered by the ablation of caspase-11 gene. Thus, although caspases may contribute to certain aspects of pathology in this mouse model of ALS, their inhibition is not sufficient to prevent neurodegeneration. Our study urges caution when considering the inhibition of caspases as a direct therapeutic method for the treatment of chronic neurodegenerative diseases.
Kang
Shin Jung
SJ
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sanchez
Ivelisse
I
Jing
Naisen
N
Yuan
Junying
J
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D020170:Caspase 1 / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000473:pathology; D007375:Interleukin-1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013116:Spinal Cord / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D015996:Survival Rate
D007375:Interleukin-1; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C101136:Casp4 protein, mouse; D053148:Caspase 3; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1