β - N -methylamino- L -alanine induces oxidative stress and glutamate release through action on system Xc − ⁎

Department of Biomedical Sciences, Marquette University, 561 N. 15th Street, Rm 446 Milwaukee, WI 53233, USA.
Experimental Neurology (Impact Factor: 4.7). 05/2009; 217(2):429-33. DOI: 10.1016/j.expneurol.2009.04.002
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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.

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Available from: XiaoQian Liu, Oct 04, 2015
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    • "Also, there are various other studies suggesting additional modes of toxicity for BMAA. For example, BMAA may be inhibiting the cysteine/glutamate antiporter system Xc-, resulting in glutathione depletion (Liu et al., 2009). Erroneous incorporation of BMAA, a non-protein amino acid, into proteins has also been suggested as another mode of toxicity (Murch et al., 2004; Dunlop et al., 2013). "
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    ABSTRACT: The environmental neurotoxins BMAA (β-N-methylamino-L-alanine) and BOAA (β-N-oxalylamino-L-alanine) are implicated as possible causative agents for the neurodegenerative diseases, amyotrophic lateral sclerosis/ Parkinsonism/Dementia complex (ALS/PDC) and neurolathyrism, respectively. Both are structural analogs of the neurotransmitter, glutamate, and bind postsynaptic glutamate receptors. In this study, the effect of ingestion of these toxins on the response of a singly-innervated, identified, glutamatergic postsynaptic cell in a living, undissected Drosophila is observed by intracellular recording. Previously we have reported that ingested BMAA behaves as an NMDA agonist that produces an abnormal NMDA response in the postsynaptic cell. It is shown here that BOAA also behaves as an NMDA agonist, and produces an effect very similar to that of BMAA on the postsynaptic response. In response to a single stimulus, the amplitude of the NMDA component is decreased, while the time to peak and duration of the NMDA component are greatly increased. No discernable effect on the AMPA component of the response was observed. Furthermore, both BMAA and BOAA cause an NMDAR-specific desensitization in response to repetitive stimulation at the physiological frequency for the postsynaptic cell (5Hz). The possibility that this phenomenon may represent a response to excessive Ca2 + entry through NMDAR channels is discussed. This desensitization phenomenon, as well as the abnormal NMDAR gating characteristics induced by BMAA, appears to be rescued during higher frequency stimulation (e.g. 10, 20 Hz).
    Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology 12/2014; 167. DOI:10.1016/j.cbpc.2014.08.006 · 2.30 Impact Factor
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    • "L-BMAA inhibits cystine/glutamate exchange transporter (Xc-System), which mediates cystine absorption; as a consequence there is a loss of glutathione and oxidative stress increases. Moreover, this toxin appears to release glutamate via the Xc-System (Liu et al., 2009). As described above, it has been hypothesized that L-BMAA can elicit ALS-PDC. "
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    ABSTRACT: β-N-methylamino-l-alanine (L-BMAA) is a neurotoxic amino acid that has been related to various neurodegenerative diseases. The aim of this work was to analyze the biotoxicity produced by L-BMAA in vivo in rats, trying to elucidate its physiopathological mechanisms and to search for analogies between the found effects and pathologies like Amyotrophic Lateral Sclerosis (ALS). Our data demonstrated that the neurotoxic effects in vivo were dosage-dependent. For evaluating the state of the animals, a neurological evaluation scale was developed as well as a set of functional tests. Ultrastructural cell analysis of spinal motoneurons has revealed alterations both in endoplasmic reticulum and mitochondria. Since GSK3β could play a role in some neuropathological processes, we analyzed the alterations occurring in GSK3β levels in L-BMAA treated rats, we have observed an increase in the active form of GSK3β levels in lumbar spinal cord and motor cerebral cortex. On the other hand, (TAR)-DNA-binding protein 43 (TDP-43) increased in L-BMAA treated animals. Our results indicated that N-acetylaspartate (NAA) declined in animals treated with L-BMAA, and the ratio of N-acetylaspartate/choline (NAA/Cho), N-acetylaspartate/creatine (NAA/Cr) and N-acetylaspartate/choline+creatine (NAA/Cho+Cr) tended to decrease in lumbar spinal cord and motor cortex. This project offers some encouraging results that could help establishing the progress in the development of an animal model of sporadic ALS and L-BMAA could be a useful tool for this purpose.
    04/2013; 36(2):243-255. DOI:10.1016/j.etap.2013.04.007
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    • "It has been repeatedly suggested that exposure to BMAA is also associated with the development of other neurodegenerative disorders, such as Alzheimer's disease (AD)4567. Numerous in vitro investigations conducted on mice, rat, leech, and recently human cells, have revealed the detrimental effects of BMAA to neurons891011121314151617. Excitotoxicity, the process of cell death occurring due to activation of excitatory amino acid (EAA) receptors (notably glutamate receptors), is the most commonly implicated mechanism of action for this naturally occurring compound891011121314151617. "
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    ABSTRACT: The amino acid variant β-methyl-amino-L-alanine (BMAA) has long been associated with the increased incidence and progression of the amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC). Previous studies have indicated that BMAA damages neurons via excitotoxic mechanisms. We have challenged rat olfactory ensheathing cells (OECs) with exogenous BMAA and found it to be cytotoxic. BMAA also induces a significant increase in Ca(2+) influx, enhanced production of reactive oxygen species (ROS), and disrupts mitochondrial activity in OECs. This is the first study investigating BMAA toxicity using pure glial cells. These findings align BMAA with the three proposed mechanisms of degeneration in ALS, those being non-cell autonomous death, excitotoxicity and mitochondrial dysfunction.
    Scientific Reports 03/2013; 3:1482. DOI:10.1038/srep01482 · 5.58 Impact Factor
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