Did Free Radicals Kill Lou Gehrig? Insights into the Complex Role of Peroxynitrite in Disease
Mutations to the antioxidant enzyme superoxide dismutase (SOD) were discovered 20 years ago to cause ALS, but its role remains enigmatic. New insights reveal that ALS-causing mutations frustrate metal binding to SOD. When SOD is missing its key metal cofactors, it can induce a cascade of events that triggers the death of motor neurons that involves the oxidant peroxynitrite (ONOO-), tyrosine nitration of HSP90, activation of the extracellular ATP receptor P2X7 and activation of a FAS-dependent apoptotic pathway.
In support of the role of metal-deficient SOD, Dr. Joseph Beckman’s laboratory has shown that the copper-delivery agent CuATSM, currently used in humans as a PET imaging agent, is extraordinarily effective in treating mouse models of ALS based upon SOD. Lifespans have been extended from 130 days to more than 600 days, with most mice still surviving.