Résumé :
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Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neuromuscular disease characterized by selective degeneration of upper and lower motor neurons, progressive muscle wasting, and paralysis. Some familial cases are caused by missense mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD1), a free radical-scavenging enzyme that protects cells against oxidative stress. Because it is thought that the first motor symptoms result from premature damage to the distal part of the motor unit, we recently analysed gene expression in skeletal muscle of mutant SOD1 (G86R) mice using a high-density oligonucleotide microarray approach. One of the strongest regulations detected concerned Ras-related associated with diabetes (Rad), a small GTPase of the Ras superfamily. In the present study, we analyzed the expression of Rad during the course of the disease in G86R mice and related this expression to the presence of denervation and oxidative stress at early stages of the muscle pathology in ALS. Our findings indicate that the increase in muscle Rad expression is early and age-dependent, occurs within adult muscle fibers, and is also present in patients with sporadic ALS. We also show that Rad is not only stimulated by muscle denervation but also in response to an ischemia/reperfusion stress, which generates high levels of reactive oxygen species. Interestingly, both Rad up-regulation and increase amounts of reactive oxygen species were detected early in asymptomatic G86R mice, before the onset of denervation. Therefore, these findings provide evidence for the early oxidative stress mechanisms affecting muscle in ALS.
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