SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter

The mechanism by which Cu2+/Zn2+ superoxide dismutase (SOD1) mutants lead t o motor neuron degeneration in familial amyotrophic lateral sclerosis (FALS ) is unknown. We show that oxidative reactions triggered by hydrogen peroxi de and catalyzed by A4V and I113T mutant but not wild-type SOD1 inactivated the glutamate transporter human GLT1. Chelation of the copper ion of the p rosthetic group of A4V prevented GLT1 inhibition. GLT1 was a selective targ et of oxidation mediated by SOD1 mutants, and its reactivity was confined t o the intracellular carboxyl-terminal domain. The antioxidant Mn(III)TBAP r escued GLT1 from inhibition. Because inactivation of GLT1 results in neuron al degeneration, we propose that toxic properties of SOD1 mutants lead to n euronal death via an excitotoxic mechanism in SOD1-linked FALS.