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Transport of BMAA into Neurons and Astrocytes by System xc-

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Abstract

The study of the mechanism of β-N-methylamino-l-alanine (BMAA) neurotoxicity originally focused on its effects at the N-methyl-d-aspartate (NMDA) receptor. In recent years, it has become clear that its mechanism of action is more complicated. First, there are certain cell types, such as motor neurons and cholinergic neurons, where the dominate mechanism of toxicity is through action at AMPA receptors. Second, even in cortical neurons where the primary mechanism of toxicity appears to be activation of NMDA receptors, there are other mechanisms involved. We found that along with NMDA receptors, activation of mGLuR5 receptors and effects on the cystine/glutamate antiporter (system xc-) were involved in the toxicity. The effects on system xc- are of particular interest. System xc- mediates the transport of cystine into the cell in exchange for releasing glutamate into the extracellular fluid. By releasing glutamate, system xc- can potentially cause excitotoxicity. However, through providing cystine to the cell, it regulates the levels of cellular glutathione (GSH), the main endogenous intracellular antioxidant, and in this way may protect cells against oxidative stress. We have previously published that BMAA inhibits cystine uptake leading to GSH depletion and had indirect evidence that BMAA is transported into the cells by system xc-. We now present direct evidence that BMAA is transported into both astrocytes and neurons through system xc-. The fact that BMAA is transported by system xc- also provides a mechanism for BMAA to enter brain cells potentially leading to misincorporation into proteins and protein misfolding.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Marquette University, 561 N. 15th Street, Rm 426, Milwaukee, WI, 53233, USA

    Rebecca Albano & Doug Lobner

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  1. Rebecca Albano
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  2. Doug Lobner
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Correspondence to Doug Lobner.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with ethical standards of the institution or practice at which the studies were conducted.

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Albano, R., Lobner, D. Transport of BMAA into Neurons and Astrocytes by System xc-. Neurotox Res 33, 1–5 (2018). https://doi.org/10.1007/s12640-017-9739-4

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  • DOI: https://doi.org/10.1007/s12640-017-9739-4

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