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beta-N-methylamino-l-alanine induces oxidative stress and glutamate release through action on system Xc(-).
Exp Neurol. 2009 Jun; 217(2):429-33.EN

Abstract

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.

Authors+Show Affiliations

Department of Biomedical Sciences, Marquette University, 561 N. 15th Street, Rm 446 Milwaukee, WI 53233, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19374900

Citation

Liu, Xiaoqian, et al. "Beta-N-methylamino-l-alanine Induces Oxidative Stress and Glutamate Release Through Action On System Xc(-)." Experimental Neurology, vol. 217, no. 2, 2009, pp. 429-33.
Liu X, Rush T, Zapata J, et al. Beta-N-methylamino-l-alanine induces oxidative stress and glutamate release through action on system Xc(-). Exp Neurol. 2009;217(2):429-33.
Liu, X., Rush, T., Zapata, J., & Lobner, D. (2009). Beta-N-methylamino-l-alanine induces oxidative stress and glutamate release through action on system Xc(-). Experimental Neurology, 217(2), 429-33. https://doi.org/10.1016/j.expneurol.2009.04.002
Liu X, et al. Beta-N-methylamino-l-alanine Induces Oxidative Stress and Glutamate Release Through Action On System Xc(-). Exp Neurol. 2009;217(2):429-33. PubMed PMID: 19374900.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - beta-N-methylamino-l-alanine induces oxidative stress and glutamate release through action on system Xc(-). AU - Liu,Xiaoqian, AU - Rush,Travis, AU - Zapata,Jasmine, AU - Lobner,Doug, Y1 - 2009/04/15/ PY - 2009/01/06/received PY - 2009/03/12/revised PY - 2009/04/07/accepted PY - 2009/4/21/entrez PY - 2009/4/21/pubmed PY - 2009/7/8/medline SP - 429 EP - 33 JF - Experimental neurology JO - Exp. Neurol. VL - 217 IS - 2 N2 - 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. SN - 1090-2430 UR - https://www.unboundmedicine.com/medline/citation/19374900/beta_N_methylamino_l_alanine_induces_oxidative_stress_and_glutamate_release_through_action_on_system_Xc____ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(09)00137-X DB - PRIME DP - Unbound Medicine ER -