Figure 4.

Multiple mechanisms of L-BMAA cellular toxicity. L-BMAA in the presence of bicarbonate ions (HCO3-) forms L-BMAA’s carbamate adduct, named β-carbamate, and binds to ionotropic (iGluR) and metabotropic (mGluR) receptors. The activation of iGluR and mGluR leads to a significant increase in intracellular Ca₂⁺, directly via iGluR and indirectly via mGluR (PLC signaling). This Ca₂⁺ increase promotes mitochondrial reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress. L-BMAA inhibits the cystine/glutamate antiporter (system Xc-)-mediated cystine uptake, which leads to glutathione depletion and increased oxidative stress. Once in the cytoplasm, the toxin is likely to be inserted into the neosynthesized cellular proteins and to prompt protein misfolding that often leads to the formation of insoluble aggregates, containing among other proteins TDP-43. iGluR: ionotropic glu receptors; mGluR: metabotropic glu receptors; PLC: phospholipase C; TDP-43: TAR DNA-binding protein 43.