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

被引:219
作者
Trotti, D
Rolfs, A
Danbolt, NC
Brown, RH
Hediger, MA
机构
[1] Harvard Univ, Brigham & Womens Hosp, Sch Med,Dept Med, Membrane Biol Program, Boston, MA 02115 USA
[2] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Renal, Boston, MA 02115 USA
[3] Univ Oslo, Inst Basic Med Sci, Dept Anat, N-0317 Oslo, Norway
[4] Harvard Univ, Massachusetts Gen Hosp E, Sch Med, Day Neuromuscular Res Lab, Charlestown, MA 02129 USA
关键词
D O I
10.1038/8091
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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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收藏
页码:427 / 433
页数:7
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