Redox modifier genes in amyotrophic lateral sclerosis in mice

Abstract

Amyotrophic lateral sclerosis (ALS), one of the most common adult-onset neurodegenerative diseases, has no known cure. Enhanced redox stress and inflammation have been associated with the pathoprogression of ALS through a poorly defined mechanism. Here we determined that dysregulated redox stress in ALS mice caused by NADPH oxidases Nox1 and Nox2 significantly influenced the progression of motor neuron disease caused by mutant SOD1 G93A expression. Deletion of either Nox gene significantly slowed disease progression and improved survival. However, 50% survival rates were enhanced significantly more by Nox2 deletion than by Nox1 deletion. Interestingly, female ALS mice containing only 1 active X-linked Nox1 or Nox2 gene also had significantly delayed disease onset, but showed normal disease progression rates. Nox activity in spinal cords from Nox2 heterozygous female ALS mice was approximately 50% that of WT female ALS mice, suggesting that random X-inactivation was not influenced by Nox2 gene deletion. Hence, chimerism with respect to Noxexpressing cells in the spinal cord significantly delayed onset of motor neuron disease in ALS. These studies define what we believe to be new modifier gene targets for treatment of ALS.

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

“…G93A ALS transgenic mice on a B6SJL hybrid background (90). In this study, homozygous deletion of either Nox1 or Nox2 significantly delayed disease onset, and enhanced the survival of hemizygous SOD1…”

“…G93A ALS mice, consistent with changes in disease onset (90). Although these studies differed with respect to the magnitude of their findings, collectively they led to the conclusion that both Nox1 and Nox2 are NADPH oxidase isoforms that influence disease progression in the SOD1 G93A ALS mouse model, but that Nox2 plays a more major role.…”

“…The reason for differences in outcomes between the abovedescribed studies (90,141) remains unclear, but likely has to do with background variation in the mice used to study Nox2 involvement. Indeed, differences in genetic background have been shown to influence the survival of hemizygous SOD1 G93A transgenic mice (58,139), with a 14-28 day increase in survival on the C57BL=6 congenic, as compared to the B6SJL hybrid, background.…”

“…G93A , in animal models has provided important insights into the mechanism underlying the dominant, or toxic gain-of-function, phenotype and its potential to lead to oxidative damage (55,90). Similarly, research on a rare juvenile form of ALS caused by mutations in the ALS2 gene has uncovered potential new paradigms for pathogenesis (26,54,144).…”

Les cellules gliales

“…Les astrocytes ont le pouvoir de nettoyer l'environnement synaptique du surplus de glutamate auquel les motoneurones sont particulièrement sensibles [11]. Le fait qu'une perte des transporteurs astrocytaires au glutamate est observée dans les modèles de rats et de souris ainsi que chez les patients atteints de SLA [12,13] [14][15][16][17], de même que le remplacement des cellules microgliales/macrophages exprimant la SOD1 mutée par des cellules contrôles [18,19], entraînent une augmentation notable de la survie des souris SLA.…”