Analysis of BMAA enantiomers in cycads, cyanobacteria, and mammals: in vivo formation and toxicity of d-BMAA
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Chronic dietary exposure to the cyanobacterial toxin β-N-methylamino-l-alanine (BMAA) triggers neuropathology in non-human primates, providing support for the theory that BMAA causes a fatal neurodegenerative illness among the indigenous Chamorro people of Guam. However, since there are two stereoisomers of BMAA, it is important to know if both can occur in nature, and if so, what role they might play in disease causation. As a first step, we analysed both BMAA enantiomers in cyanobacteria, cycads, and in mammals orally dosed with l-BMAA, to determine if enantiomeric changes could occur in vivo. BMAA in cyanobacteria and cycads was found only as the l-enantiomer. However, while the l-enantiomer in mammals was little changed after digestion, we detected a small pool of d-BMAA in the liver (12.5%) of mice and in the blood plasma of vervets (3.6%). Chiral analysis of cerebrospinal fluid of vervets and hindbrain of mice showed that the free BMAA in the central nervous system was the d-enantiomer. In vitro toxicity investigations with d-BMAA showed toxicity, mediated through AMPA rather than NMDA receptors. These findings raise important considerations concerning the neurotoxicity of BMAA and its relationship to neurodegenerative disease.
KeywordsChiral Enantiomer Neurodegenerative disease ALS/PDC Alzheimer’s Neurotoxicity
We acknowledge support from the John and Josephine Louis Foundation and the Deerbrook Charitable Trust. PBW acknowledges the use of the EPSRC UK National Mass Spectrometry Facility at Swansea University.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed and the appropriate institutional reviews and permissions were granted before the study was conducted.
- Ariyoshi M, Katane M, Hamase K, Miyoshi Y, Nakane M, Hoshino A, Okawa Y, Mita Y, Kaimoto S, Uchihashi M, Fukai K, Ono K, Tateishi S, Hato D, Yamanaka R, Honda S, Fushimura Y, Iwai-Kanai E, Ishihara N, Mita M, Homma H, Matoba S (2017) d-Glutamate is metabolized in the heart mitochondria. Sci Rep 7:43911. doi: 10.1038/srep43911 CrossRefPubMedPubMedCentralGoogle Scholar
- Banack SA, Metcalf JS, Jiang L, Craighead D, Ilag L, Cox PA (2012) Cyanobacteria produce N-(2-aminoethyl)glycine, a backbone for peptide nucleic acids which may have been the first genetic molecules for life on earth. PLoS One 7(11):e49043. doi: 10.1371/journal.pone.0049043 CrossRefPubMedPubMedCentralGoogle Scholar
- Bradley WG (2009) Possible therapy for ALS based on the cyanobacteria/BMAA hypothesis. Amyotrophic Lateral Scler 10(S2):114–123Google Scholar
- Cox PA, Davis DA, Mash DC, Metcalf JS, Banack SA (2016b) Do vervets and macaques respond differently to BMAA? Neurotoxicology 57:310-311 doi: 10.1016/j.neuro.2016.04.017.s
- de Munck E, Muñoz-Sáez E, Miguel BG, Solas MT, Ojeda I, Martínez A, Gil C, Arahuetes RM (2013) β-N-methylamino-l-alanine causes neurological and pathological phenotypes mimicking amyotrophic lateral sclerosis (ALS): the first step towards an experimental model for sporadic ALS. Environ Toxicol Pharmacol 36:243–255CrossRefPubMedGoogle Scholar
- Dunlop RA, Cox PA, Banack SA, Rodgers KJ (2013) The non-protein amino acid BMAA is misincorporated into human proteins in place of l-serine causing protein misfolding and aggregation. PLoS One. doi:10.371/journal.pone.0075376Google Scholar
- Euerby MR, Partridge LZ, Nunn PB (1989) Resolution of neuroactive non-protein amino acid enantiomers by high-performance liquid chromatography utilizing pre-column derivatisation with o-phthaldialdehyde-chiral thiols. Application to 2-amino-ω-phosphoalkanoic acid homologues and α-amino-β-N-methylaminopropanoic acid (β-methylaminoalanine). J Chromatogr 469:412–419CrossRefPubMedGoogle Scholar
- Karlsson O, Berg A-L, Hanrieder J, Amerup G, Lindström A-K, Brittebo EB (2015) Intracellular fibril formation, calcification, and enrichment of chaperones, cytoskeletal, and intermediate filament proteins in the adult hippocampus CA1 following neonatal exposure to the nonprotein amino acid BMAA. Arch Toxicol 89:423–436CrossRefPubMedGoogle Scholar
- National Research Council (1996) Guide for the Care and Use of Laboratory Animals. The National Academies Press, Washington, DC. doi:https://doi.org/10.17226/5140