DNA laddering and caspase 3-like activity in the spinal cord of a mouse offamilial amyotrophic lateral sclerosis

Transgenic mice with several copies of a mutated human superoxide dismutase 1 (Gly(93)-->Ala substitution) gene, i.e. a mutation responsible for the d evelopment of familial amyotrophic lateral sclerosis (ALS), integrated into the mouse genome, develop a slowly progressive paralysis of the hind-limbs accompanied by a corresponding degeneration of spinal cord neuronal tissue . We have used two different Lines of these transgenic mice [a low (similar to 12 copies) or a high (similar to 24) copy number of the mutated human s uperoxide dismutase 1 gene] to find evidence of programmed cell death in af fected spinal cord tissue at distinct age groups. Hallmarks of programmed c ell death, i.e. DNA laddering and an increase in caspase 3-like activity, w ere found in the spinal cord of both lines of mice. Behavioural evaluation of the mice indicated that the hallmarks of programmed cell death were main ly, but not exclusively found in symptomatic animals just before or at end- stage. These data suggest that programmed cell death may play a role in the disease process of familial ALS particularly in its terminal phase.