beta-N-methylamino-l-alanine induces oxidative stress and glutamate release through action on system Xc(-).
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.
Department of Biomedical Sciences, Marquette University, 561 N. 15th Street, Rm 446 Milwaukee, WI 53233, USA.
Xiaoqian
X
Liu
Travis
T
Rush
Jasmine
J
Zapata
Doug
D
Lobner
D027182:Amino Acid Transport System y+ / Q000187:drug effects* / Q000378:metabolism; D000599:Amino Acids, Diamino / Q000378:metabolism / Q000633:toxicity*; D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018920:Coculture Techniques; D000087522:Cyanobacteria Toxins; D003553:Cystine / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism / Q000633:toxicity*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism
D027182:Amino Acid Transport System y+; D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D018690:Excitatory Amino Acid Agonists; C578936:Grm5 protein, mouse; D009498:Neurotoxins; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C492255:Slc7a11 protein, mouse; C001824:beta-N-methylamino-L-alanine; D018698:Glutamic Acid; D003553:Cystine; D005978:Glutathione