β-N-methylamino-L-alanine induces oxidative stress and glutamate release through action on system Xc-
β-N-methylamino-L-alanine induces oxidative stress and glutamate release through action on system Xc-
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DOI：
10.1016/j.expneurol.2009.04.002
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发表时间：
2009-06-01
影响因子：
5.3
通讯作者：
Lobner, Doug
中科院分区：
文献类型：
--
作者：
Liu, XiaoQian;Rush, Travis;Lobner, Doug
beta-N-methylamino-L-alanine (BMAA) is a non-protein amino acid implicated in the neurodegenerative disease amyotrophic lateral sclerosis/Parkinson-dementia complex (ALS/PDC) on Guam. BMAA has recently been discovered in the brains of Alzheimer's patients in Canada and is produced by various species of cyanobacteria around the world. These findings suggest the possibility that BMAA may be of concern not only for specific groups of Pacific Islanders, but for a much larger population. Previous studies have indicated that BMAA can act as an excitotoxin by acting on the NMDA receptor. We have shown that the mechanism of neurotoxicity is actually three-fold; it involves not only direct action on the NMDA receptor, but also activation of metabotropic glutamate receptor 5 (mGluR5) and induction of oxidative stress. We now explore the mechanism by which BMAA activates the mGluR5 receptor and induces oxidative stress. We found that BMAA inhibits the cystine/glutamate antiporter (system Xc(-)) mediated cystine uptake, which in turn leads to glutathione depletion and increased oxidative stress. BMAA also appears to drive glutamate release via system Xc(-) and this glutamate induces toxicity through activation of the mGluR5 receptor. Therefore, the oxidative stress and mGluR5 activation induced by BMAA are both mediated through action at system Xc(-). The multiple mechanisms of BMAA toxicity, particularly the depletion of glutathione and enhanced oxidative stress, may account for its ability to induce complex neurodegenerative diseases. (C) 2009 Elsevier Inc. All rights reserved.
