Increased reactive oxygen species in familial amyotrophic lateral sclerosis with mutations in SOD1

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder characterized by degeneration of Large motor neurons of the brain and spinal cord. A subset of ALS is inherited (familial ALS, FALS) and is associated with more than 70 different mutations in the SOD1 gene. Here we report that lymphoblast cell lines derived from FALS patients with 16 different mutations in SOD1 gene exhibit significant increase of intracellular reactive oxygen species (ROS) compared with sporadic ALS (SALS) and normal controls (spouses of ALS patients). The ROS generation did not correlate with SOD1 activity. Further, cells incubated with vitamin C, catalase or the flavinoid quercetin 4-triazole resulted in a ten-fold increase of ROS in all groups. signifcantly reduced ROS in all groups. The catalase inhibitor 3-amino-1,2,4-Neither L-nitroarginine. a nitric oxide synthase inhibitor or vitamin E altered the ROS levels. Thus, these studies suggest that hydrogen peroxide (H2O2) is a major ROS elevated in FALS lymphoblasts and it may contribute to the degeneration of susceptible cells. Further, we postulate a mechanism by which increased H2O2 could be generated by mutant SOD1, (C) 2000 Elsevier Science B.V. All rights reserved.