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XB-ART-13044
Nat Neurosci 1999 May 01;25:427-33. doi: 10.1038/8091.
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SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter.

Trotti D , Rolfs A , Danbolt NC , Brown RH , Hediger MA .


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The mechanism by which Cu2+/Zn2+ superoxide dismutase (SOD1) mutants lead to motor neuron degeneration in familial amyotrophic lateral sclerosis (FALS) is unknown. We show that oxidative reactions triggered by hydrogen peroxide 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 prosthetic group of A4V prevented GLT1 inhibition. GLT1 was a selective target of oxidation mediated by SOD1 mutants, and its reactivity was confined to the intracellular carboxyl-terminal domain. The antioxidant Mn(III)TBAP rescued GLT1 from inhibition. Because inactivation of GLT1 results in neuronal degeneration, we propose that toxic properties of SOD1 mutants lead to neuronal death via an excitotoxic mechanism in SOD1-linked FALS.

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Species referenced: Xenopus laevis
Genes referenced: sod1

???displayArticle.disOnts??? amyotrophic lateral sclerosis
???displayArticle.omims??? AMYOTROPHIC LATERAL SCLEROSIS 1; ALS1