SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter.
Nat Neurosci
; 2(5): 427-33, 1999 May.
Article
em En
| MEDLINE
| ID: mdl-10321246
ABSTRACT
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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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Superóxido Dismutase
/
Neuroglia
/
Transportadores de Cassetes de Ligação de ATP
/
Esclerose Lateral Amiotrófica
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Neurosci
Assunto da revista:
NEUROLOGIA
Ano de publicação:
1999
Tipo de documento:
Article
País de afiliação:
Estados Unidos