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Nat Neurosci. May 1, 1999; 2 (5): 427-33.

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

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

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.

PubMed ID: 10321246
Article link: Nat Neurosci.
Grant support: 1PO1NS31248-05 NINDS NIH HHS , 5F32HS10064 AHRQ HHS, NS32001 NINDS NIH HHS , 754 Telethon, TI_754 Telethon

Genes referenced: sod1

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