Abstract
β-methylamino-L-alanine (BMAA) has been linked to several interrelated neurodegenerative diseases. Despite considerable research, specific contributions of BMAA toxicity to neurodegenerative diseases remain to be fully resolved. In the present study, we utilized state-of-the-art high-resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR), applied to intact zebrafish (Danio rerio) embryos, as a model of vertebrate development, to elucidate changes in metabolic profiles associated with BMAA exposure. Complemented by several alternative analytical approaches (i.e., in vivo visualization and in vitro assay), HRMAS NMR identified robust and dose-dependent effect of BMAA on several relevant metabolic pathways suggesting a multifaceted toxicity of BMAA including: (1) localized production of reactive oxygen species (ROS), in the developing brain, consistent with excitotoxicity; (2) decreased protective capacity against excitotoxicity and oxidative stress including reduced taurine and glutathione; (3) inhibition of several developmentally stereotypical energetic and metabolic transitions, i.e., metabolic reprogramming; and (4) inhibition of lipid biosynthetic pathways. Matrix-assisted laser desorption time-of-flight (MALDI-ToF) mass spectrometry further identified specific effects on phospholipids linked to both neural development and neurodegeneration. Taken together, a unified model of the neurodevelopmental toxicity of BMAA in the zebrafish embryo is presented in relation to the potential contribution of BMAA to neurodegenerative disease.
Highlights
Numerous studies have supported the proposed link between BMAA and ND, the toxicity of the compound, in relation to these diseases, remains to be clarified
Sustained agonistic interaction of BMAA with glutamate receptors (GluR) leads to post-synaptic excitotoxicity via influx of Ca2+, and subsequent oxidative stress resulting from production of reactive oxygen species (ROS) by mitochondria
In order to further elucidate the toxicity of BMAA, we utilized the zebrafish (Danio rerio) embryo, as a toxicological model, coupled to nuclear magnetic resonance (NMR)-based metabolomics techniques, and high-resolution magic-angle spinning (HRMAS) NMR, as a novel means to identify metabolic changes associated with exposure to the toxin
Summary
Numerous studies have supported the proposed link between BMAA and ND, the toxicity of the compound, in relation to these diseases, remains to be clarified. It has been suggested that ribosomal misincorporation of BMAA into proteins may lead to accumulation of protein aggregates (e.g., fibrils, amyloid plaques) which are a hallmark - and putative etiological agent - of the various neurodegenerative diseases. This misincorporation has been shown most recently by radioactive labeling studies in vivo[8], and previously in cellular systems[7], as well as in vitro protein synthesis experiments[9]. A unified model of the neurodevelopmental toxicity of BMAA is proposed
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