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: 4.62). 05/2009; 217(2):429-33. DOI: 10.1016/j.expneurol.2009.04.002
Source: PubMed

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.

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Available from: XiaoQian Liu, Aug 21, 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 01/2014; 167. DOI:10.1016/j.cbpc.2014.08.006 · 2.83 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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    • "4), the finding that low concentrations of l-BMAA adversely effect cellular protein homeostasis via ER stress, ROS, protein oxidation, and ubiquitination appears to be a general phenomenon in human cells. It is important to note that l-BMAA-induced ROS and ROS-associated protein oxidation were at least partially rescued via coincubation with the ROS scavenger vitamin E (Figs. 2E and 2G), as also observed previously by Liu et al. (2009) in cortical cell cultures of mice. This, however, was not the case for the l-BMAA-induced ubiquitination and increased caspase 12 and 20S proteasomal activity (Figs. "
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    ABSTRACT: The cyanobacterial L-BMAA (β-N-methylamino-L-alanine) is described as a low potency excitotoxin, possibly a factor in the increased incidence of amyotrophic lateral sclerosis (ALS) and Parkinsonism dementia complex (PDC) on Guam. The latter association is intensively disputed, as L-BMAA concentrations required for toxic effects exceed those assumed to occur via food. The question thus was raised whether L-BMAA leads to neurodegeneration at non-excitotoxic conditions. Using human SH-SY5Y neuroblastoma cells, L-BMAA-transport, incorporation into proteins and subsequent impairment of cellular protein homeostasis were investigated. Binding of L-BMAA to intracellular proteins, but no clear protein incorporation was detected in response to (14)C-L-BMAA exposures. Nevertheless, low L-BMAA concentrations (≥0.1 mM, 48 hours) increased protein ubiquitination, 20S proteasomal and caspase 12 activity, expression of the ER-stress marker CHOP, and enhanced phosphorylation of elf2α in SH-SY5Y. In contrast, high L-BMAA concentrations (≥1 mM, 48 hours) increased ROS and protein oxidization, which were partially ameliorated by co-incubation vitamin E. L-BMAA mediated cytotoxicity was observable 48 hours following ≥2 mM L-BMAA treatment. Consequently, the data presented here suggest that low L-BMAA concentrations result in a dysregulation of the cellular protein homeostasis with ensuing ER stress that is independent from high concentration effects such as excitotoxicity and oxidative stress. Thus, the latter could be a contributing factor in the onset and slow progression of ALS/PDC on Guam.
    Toxicological Sciences 10/2012; 131(1). DOI:10.1093/toxsci/kfs291 · 4.48 Impact Factor
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