Figure 5 | Scientific Reports

Figure 5

From: Metabolic profiling of zebrafish (Danio rerio) embryos by NMR spectroscopy reveals multifaceted toxicity of β-methylamino-L-alanine (BMAA)

Figure 5

Proposed model of the multifaceted toxicity of BMAA in the central nervous system as evidenced by observed changes in metabolic profile in the zebrafish embryo model, and supported by previous studies. As previously shown6 BMAA disrupts Ca2+ homeostasis in neurons via agonistic interactions with GluR, causing mitochondrial dysfunction including release of ROS. Increase in ROS was prominent in the brain region of BMAA170 treated embryo (Fig. 3A) which is consistent with excitotoxic mitochondrial dysfunction. This excitotoxicity subsequently interferes with stereotypical metabolic transitions (i.e., metabolic reprogramming) associated with neuronal differentiation27 as suggested in the current study by increased glycolysis (i.e., decrease in glucose, and increase in lactate), glutaminolysis (i.e., decrease in Glu and Gln, and increase in Ala and Gln/Glu ratio) and serinolysis (i.e., increase in Ala, and decrease in Gly) in BMAA-treated embryos (Fig. 2D). It has been previously shown that BMAA inhibits the Cyst/Glu antiporter (Xc¯) of astroglia which limits supply of Cys for biosynthesis of both GSH and Tau to the neuron10, and consequently exacerbates oxidative stress (i.e., ROS production) and disruption of Ca2+ homeostasis, respectively. Glutathione depletion is observed in the present study (Figs 2D and 3B), and likely compounded by reduced levels (Fig. 2D) of Gly (via serinolysis) and Glu (via glutaminolysis) as biosynthetic precursors of GSH. Reduction of Gln would, in addition, lead to reduction of the essential neurotransmitters, Glu and GABA. Mitochondrial dysfunction additionally reduces production of NAA (Fig. 2D) which is the biosynthetic precursor of lipid metabolism. Consistent with reduced NAA, both FA and Chol were significantly decreased (Figs 2D and 4B). NAA is produced in the mitochondria of neurons, and transported to oligodendrocytes where it is metabolized into Asp and acetate; acetate is utilized for the synthesis of FA and Chol which, in turn, are utilized for myelin synthesis, as well as essential components of cell membranes, and key regulatory molecules. Among the lipids characterized by HPTCL/MALDI-ToF (Fig. 4C–D), phospholipids levels were affected by BMAA: PE increased, and PI decreased. The former may be linked to a compensatory increase in the synthesis of EA, and the latter to metabolic diversion of the m-Ins precursor (G6P) by elevated glycolysis. Observed increases and decreases in metabolites shown by arrows (i.e., ↑ and ↓, respectively). Pathways elevated by BMAA, according to the proposed model indicated by heavy lines, and those attenuated by dashed lines. Pathways associated with metabolic reprogramming by BMAA colored as follows: blue = glycolysis, red = glutaminolysis and green = serinolysis. Abbreviations: glucose-6-phosphate (G6P); glyceraldehyde-3-phosphate (G3P); pyruvate (Pyr); malic acid (Mal); fumaric acid (Fum); succinic acid (Suc); α-ketoglutarate (αKg); D-isocitrate (D-Isocit); cis-aconitate (cAco); citric acid (Cit); oxaloacetic acid (OAA); glutamate pyruvate transaminase (GPT); glutamate receptors (Glu-R); excitatory amino acid receptor (EAAT); tricarboxylic acid cycle (TCA).

Back to article page