Neurotoxicity Research

, Volume 36, Issue 3, pp 602–611 | Cite as

The Cyanotoxin and Non-protein Amino Acid β-Methylamino-L-Alanine (L-BMAA) in the Food Chain: Incorporation into Proteins and Its Impact on Human Health

  • Rachael A. DunlopEmail author
  • Gilles J. Guillemin
Review Article


The size and frequency of cyanobacterial blooms are increasing concomitantly with rising global temperatures and increased eutrophication, and this has implications for human health. Cyanotoxins, including L-BMAA, have been implicated in triggering neurodegenerative diseases such as ALS/PDC and Alzheimer’s disease. L-BMAA is a water-soluble non-protein amino acid that can bioaccumulate up the food chain, in a free- and protein-bound form. While some data exists on the degree of environmental enrichment of L-BMAA in water bodies, cyanobacteria-derived supplements, fruit bats, and seafood, virtually nothing is known about the presence of L-BMAA in other foodstuffs. It has now been shown several times in laboratory settings that plants can absorb L-BMAA into their leaves and stems, but data from wild-grown plants is nascent. One of the mechanisms implicated in L-BMAA bioaccumulation is misincorporation into proteins in the place of the canonical amino acid L-serine. We first identified this as a mechanism of action of L-BMAA in 2013, and since then, several groups have replicated these findings, but others have not. Here, we discuss in detail the experimental approaches, why they may have produced negative findings and propose several ways forward for developing consistency within the field. We emphasize the need to standardize cell culture methods, using L-serine-free medium to study misincorporation of BMAA, and urge accurate reporting of the components present in cell culture media.


L-BMAA L-serine Misincorporation Protein incorporation Cyanobacteria Cyanotoxins Neurodegeneration 



Alzheimer’s disease


N-(2-aminoethyl) glycine


Amyotrophic lateral sclerosis


Amyotrophic lateral sclerosis-parkinsonism-dementia type complex


6-Aminoquinolyl-N-hydroxysccinimidyl carbamate








2,4-Diaminobutyric acid


dihydrofolate reductase




Hank’s buffered salt solution


Hydrochloric acid


Hydrophilic interaction liquid chromatography


High-performance liquid chromatography with tandem mass spectrometry


Liquid chromatography and tandem mass spectrometry


Motor neuron disease


messenger RNA


sodium-dodecyl sulfate


Sodium dodecyl sulfate polyacrylamide gel electrophoresis


trichloroacetic acid



The authors thank Ms. Gracie McKanna for producing Fig. 1, Dr. Paul A. Cox for careful editing of this manuscript and Dr. Sandra Banack for her input.

Funding Information

Professor Guillemin is funded by the Australian Research Council, Deb Bailey Foundation, MND and Me Foundation, Fight MND Foundation and Macquarie University. Doctor Rachael Dunlop’s research was funded, in part, by an equipment grant from The William Stamps Farish Fund.


  1. Almuhtaram H, Cui Y, Zamyadi A, Hofmann R (2018) Cyanotoxins and cyanobacteria cell accumulations in drinking water treatment plants with a low risk of bloom formation at the source. Toxins (Basel) 10.
  2. Al-Sammak M, Hoagland K, Cassada D, Snow D (2014) Co-occurrence of the cyanotoxins BMAA, DABA and Anatoxin-a in Nebraska reservoirs, fish, and aquatic plants. Toxins (Basel) 6:488–508. CrossRefGoogle Scholar
  3. Andersson M, Karlsson O, Bergström U, Brittebo EB, Brandt I (2013) Maternal transfer of the cyanobacterial neurotoxin β-N-Methylamino-L-alanine (BMAA) via Milk to suckling offspring. PLoS One 8:e78133. CrossRefGoogle Scholar
  4. Andersson M, Karlsson O, Brandt I (2018) The environmental neurotoxin β-N-methylamino-L-alanine (L-BMAA) is deposited into birds’ eggs. Ecotoxicol Environ Saf 147:720–724. CrossRefGoogle Scholar
  5. Banack SA, Cox PA (2003) Biomagnification of cycad neurotoxins in flying foxes: implications for ALS-PDC in Guam. Neurology 61:387–389CrossRefGoogle Scholar
  6. Banack SA, Murch SJ (2009) Multiple neurotoxic items in the Chamorro diet link BMAA with ALS/PDC. Amyotroph Lateral Scler 10(Suppl 2):34–40. CrossRefGoogle Scholar
  7. Banack SA, Murch SJ, Cox PA (2006) Neurotoxic flying foxes as dietary items for the Chamorro people, Marianas Islands. J Ethnopharmacol 106:97–104. CrossRefGoogle Scholar
  8. Bell E, Vega A, Nunn PB, (1967). A neurotoxic amino acid in seeds of Cycas Circulanis. Fifth cycad Conf. X1-1–7Google Scholar
  9. Beri J, Nash T, Martin RM, Bereman MS (2017) Exposure to BMAA mirrors molecular processes linked to neurodegenerative disease. Proteomics 17:17–18. CrossRefGoogle Scholar
  10. Bishop SL, Kerkovius JK, Menard F, Murch SJ (2018) N-β-Methylamino-L-alanine and its naturally occurring isomers in cyanobacterial blooms in Lake Winnipeg. Neurotox Res 33:133–142. CrossRefGoogle Scholar
  11. Brand LE, Pablo J, Compton A, Hammerschlag N, Mash DC (2010) Cyanobacterial blooms and the occurrence of the neurotoxin beta-N-methylamino-L-alanine (BMAA) in South Florida aquatic food webs. Harmful Algae 9:620–635. CrossRefGoogle Scholar
  12. Chatziefthimiou AD, Deitch EJ, Glover WB, Powell JT, Banack SA, Richer RA, Cox PA, Metcalf JS (2018) Analysis of neurotoxic amino acids from marine waters, microbial Mats, and seafood destined for human consumption in the Arabian gulf. Neurotox Res 33:143–152. CrossRefGoogle Scholar
  13. Christensen SJ, Hemscheidt TK, Trapido-Rosenthal H, Laws E a, Bidigare RR (2012) Detection and quantification of b-methylamino-L-alanine in aquatic invertebrates. Limnol Oceanogr Methods 10:891–898. CrossRefGoogle Scholar
  14. Contardo-Jara V, Schwanemann T, Pflugmacher S (2014) Uptake of a cyanotoxin, β-N-methylamino-l-alanine, by wheat (Triticum aestivum). Ecotoxicol Environ Saf 104C:127–131. CrossRefGoogle Scholar
  15. Cox PA, Banack SA, Murch SJ (2003) Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proc Natl Acad Sci U S A 100:13380–13383. CrossRefGoogle Scholar
  16. Cox PA, Banack SA, Murch SJ (2007) Cyanobacteria, cycads, and neurodegenerative disease among the Chamorro people of Guam, in: memoirs of the New York botanical garden. NYGB Press.
  17. Cox PA, Davis DA, Mash DC, Metcalf JS, Banack SA (2016) Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain. Proc R Soc Lond B Biol Sci 283:20152397CrossRefGoogle Scholar
  18. Delcourt N, Claudepierre T, Maignien T, Arnich N, Mattei C (2018) Cellular and molecular aspects of the β-N-Methylamino-l-alanine (BMAA) mode of action within the neurodegenerative pathway: facts and controversy. Toxins (Basel) 10.
  19. Downing S, Banack SA, Metcalf JS, Cox PA, Downing TG (2011) Nitrogen starvation of cyanobacteria results in the production of β-N-methylamino-L-alanine. Toxicon 58:187–194. CrossRefGoogle Scholar
  20. Dunlop RA, Cox PA, Banack SA, Rodgers KJ (2013) The non-protein amino acid BMAA is incorporated into human proteins in place of L-serine causing protein misfolding and aggregation. PLoS One 8:e75376. CrossRefGoogle Scholar
  21. Dunlop RA, Main BJ, Rodgers KJ (2014) The deleterious effects of non-protein amino acids from desert plants on human and animal health. J Arid Environ 112:152–158. CrossRefGoogle Scholar
  22. Esterhuizen-Londt M, Pflugmacher S (2019) Vegetables cultivated with exposure to pure and naturally occurring β-N-methylamino-L-alanine (BMAA) via irrigation. Environ Res 169:357–361. CrossRefGoogle Scholar
  23. Garruto RM, Gajdusek DC, Chen K-M (1981) Amyotrophic lateral sclerosis and parkinsonism-dementia among Filipino migrants to Guam. Ann Neurol 10:341–350. CrossRefGoogle Scholar
  24. Glover WB, Mash DC, Murch SJ (2014) The natural non-protein amino acid N-β-methylamino-L-alanine (BMAA) is incorporated into protein during synthesis. Amino Acids 46:2553–2559. CrossRefGoogle Scholar
  25. Glover WB, Baker TC, Murch SJ, Brown P (2015) Determination of β-N-methylamino-L-alanine,N-(2-aminoethyl)glycine, and 2,4-diaminobutyric acid in Food Products Containing Cyanobacteria by Ultra-Performance Liquid Chromatography and Tandem Mass Spectrometry: Single-Laboratory Validation. J AOAC Int 98:1559–1565. CrossRefGoogle Scholar
  26. Hammerschlag N, Davis D, Mondo K, Seely M, Murch S, Glover W, Divoll T, Evers D, Mash D (2016) Cyanobacterial Neurotoxin BMAA and Mercury in Sharks. Toxins (Basel) 8:238. CrossRefGoogle Scholar
  27. Holtcamp W (2012) The emerging science of BMAA: do cyanobacteria contribute to neurodegenerative disease? Environ Health Perspect 120:A110–A116. Google Scholar
  28. Huisman J, Codd GA, Paerl HW, Ibelings BW, Verspagen JMH, Visser PM (2018) Cyanobacterial blooms. Nat Rev Microbiol 16:471–483. CrossRefGoogle Scholar
  29. Jiang L, Kiselova N, Rosén J, Ilag LL (2015) Quantification of neurotoxin BMAA (β-N-methylamino-L-alanine) in seafood from Swedish markets. Sci Rep 4:6931. CrossRefGoogle Scholar
  30. Jiao Y, Chen Q, Chen X, Wang X, Liao X, Jiang L, Wu J, Yang L (2013) Occurrence and transfer of a cyanobacterial neurotoxin β-methylamino-l-alanine within the aquatic food webs of Gonghu Bay (Lake Taihu, China) to evaluate the potential human health risk. Sci Total Environ 468-469C:457–463. Google Scholar
  31. Jonasson S, Eriksson J, Berntzon L, Spácil Z, Ilag LL, Ronnevi L-O, Rasmussen U, Bergman B (2010) Transfer of a cyanobacterial neurotoxin within a temperate aquatic ecosystem suggests pathways for human exposure. Proc Natl Acad Sci U S A 107:9252–9257. CrossRefGoogle Scholar
  32. Jungblut AD, Wilbraham J, Banack SA, Metcalf JS, Codd GA (2018) Microcystins, BMAA and BMAA isomers in 100-year-old Antarctic cyanobacterial mats collected during captain R.F. Scott’s discovery expedition. Eur J Phycol 53:115–121. CrossRefGoogle Scholar
  33. Karlsson O, Jiang L, Andersson M, Ilag LL, Brittebo EB (2014) Protein association of the neurotoxin and non-protein amino acid BMAA (β-N-methylamino-l-alanine) in the liver and brain following neonatal administration in rats. Toxicol Lett 226:1–5. CrossRefGoogle Scholar
  34. Krakauer J (2015). How Chris McCandless died: an update. New Yorker, February 11. Retrieved from
  35. Krakauer J, Long Y, Kolbert A, Thanedar S, Southard J (2015) Presence of L-Canavanine in Hedysarum alpinum seeds and its potential role in the death of Chris McCandless. Wilderness Environ Med 26:36–42. CrossRefGoogle Scholar
  36. Kurland LT (1988) Amyotrophic lateral sclerosis and Parkinson’s disease complex on Guam linked to an environmental neurotoxin. Trends Neurosci 11:51–54. CrossRefGoogle Scholar
  37. Lage S, Annadotter H, Rasmussen U, Rydberg S (2015) Biotransfer of β-N-methylamino-L-alanine (BMAA) in a eutrophicated freshwater lake. Mar Drugs 13:1185–1201. CrossRefGoogle Scholar
  38. Lance E, Arnich N, Maignien T, Biré R (2018) Occurrence of β-N-methylamino-l-alanine (BMAA) and isomers in aquatic environments and aquatic food sources for humans. Toxins (Basel) 10:83. CrossRefGoogle Scholar
  39. Lee JW, Beebe K, Nangle LA, Jang J, Longo-Guess CM, Cook SA, Davisson MT, Sundberg JP, Schimmel P, Ackerman SL (2006) Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration. Nature 443:50–55. CrossRefGoogle Scholar
  40. Li A, Song J, Hu Y, Deng L, Ding L, Li M (2016) New typical vector of neurotoxin β-N-Methylamino-l-alanine (BMAA) in the marine benthic ecosystem. Mar Drugs 14.
  41. Li B, Yu S, Li G, Chen X, Huang M, Liao X, Li H, Hu F, Wu J (2019) Transfer of a cyanobacterial neurotoxin, β-methylamino-L-alanine from soil to crop and its bioaccumulation in Chinese cabbage. Chemosphere 219:997–1001. CrossRefGoogle Scholar
  42. Main BJ, Bowling LC, Padula MP, Bishop DP, Mitrovic SM, Guillemin GJ, Rodgers KJ (2018) Detection of the suspected neurotoxin β-methylamino-L-alanine (BMAA) in cyanobacterial blooms from multiple water bodies in eastern Australia. Harmful Algae 74:10–18. CrossRefGoogle Scholar
  43. Manolidi K, Triantis TM, Kaloudis T, Hiskia A (2019) Neurotoxin BMAA and its isomeric amino acids in cyanobacteria and cyanobacteria-based food supplements. J Hazard Mater 365:346–365. CrossRefGoogle Scholar
  44. McCarron P, Logan AC, Giddings SD, Quilliam MA (2014) Analysis of β-N-methylamino-L-alanine (BMAA) in spirulina-containing supplements by liquid chromatography-tandem mass spectrometry. Aquat Biosyst 10:5. CrossRefGoogle Scholar
  45. Mondo K, Hammerschlag N, Basile M, Pablo J, Banack SA, Mash DC (2012) Cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) in shark fins. Mar Drugs 10:509–520. CrossRefGoogle Scholar
  46. Mondo K, Broc Glover W, Murch SJ, Liu G, Cai Y, Davis DA, Mash DC (2014) Environmental neurotoxins β-N-Methylamino-L-alanine (BMAA) and mercury in shark cartilage dietary supplements. Food Chem Toxicol 70:26–32. CrossRefGoogle Scholar
  47. Morabito S, Silvestro S, Faggio C (2018) How the marine biotoxins affect human health. Nat Prod Res 32:621–631. CrossRefGoogle Scholar
  48. Murch SJ, Cox PA, Banack SA (2004) A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc Natl Acad Sci U S A 101:12228–12231. CrossRefGoogle Scholar
  49. Nunn PB, Codd GA (2017) Metabolic solutions to the biosynthesis of some diaminomonocarboxylic acids in nature: formation in cyanobacteria of the neurotoxins 3-N-methyl-2,3-diaminopropanoic acid (BMAA) and 2,4-diaminobutanoic acid (2,4-DAB). Phytochemistry 144:253–270. CrossRefGoogle Scholar
  50. Okle O, Stemmer K, Deschl U, Dietrich DR (2012) L-BMAA induced ER stress and enhanced caspase 12 cleavage in human neuroblastoma SH-SY5Y cells at low Nonexcitotoxic concentrations. Toxicol Sci 131:217–224. CrossRefGoogle Scholar
  51. Ozawa K, Headlam MJ, Mouradov D, Watt SJ, Beck JL, Rodgers KJ, Dean RT, Huber T, Otting G, Dixon NE (2005) Translational incorporation of L-3,4-dihydroxyphenylalanine into proteins. FEBS J 272:3162–3171. CrossRefGoogle Scholar
  52. Roney BR, Renhui L, Banack SA, Murch S, Honegger R, Cox PA (2009) Consumption of fa cai Nostoc soup: a potential for BMAA exposure from Nostoc cyanobacteria in China? Amyotroph Lateral Scler 10(Suppl 2):44–49. CrossRefGoogle Scholar
  53. Salomonsson ML, Fredriksson E, Alfjorden A, Hedeland M, Bondesson U (2015) Seafood sold in Sweden contains BMAA: a study of free and total concentrations with UHPLC-MS/MS and dansyl chloride derivatization. Toxicol Rep 2:1473–1481. CrossRefGoogle Scholar
  54. Scott LL, Downing S, Downing T (2018) Potential for dietary exposure to β-N-methylamino-L-alanine and microcystin from a freshwater system. Toxicon 150:261–266. CrossRefGoogle Scholar
  55. Spencer PS, Nunn PB, Hugon J, Ludolph AC, Ross SM, Roy DN, Robertson RC (1987) Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant excitant neurotoxin. Science 237:517–522CrossRefGoogle Scholar
  56. van Onselen R, Downing S, Kemp G, Downing T (2017) Investigating β-N-methylamino-L-alanine misincorporation in human cell cultures: a comparative study with known amino acid analogues. Toxins (Basel) 9:17–27. CrossRefGoogle Scholar
  57. Violi JP, Mitrovic SM, Colville A, Main BJ, Rodgers KJ (2019) Prevalence of β-methylamino-L-alanine (BMAA) and its isomers in freshwater cyanobacteria isolated from eastern Australia. Ecotoxicol Environ Saf 172:72–81. CrossRefGoogle Scholar
  58. Wells ML, Trainer VL, Smayda TJ, Karlson BSO, Trick CG, Kudela RM, Ishikawa A, Bernard S, Wulff A, Anderson DM, Cochlan WP (2015) Harmful algal blooms and climate change: learning from the past and present to forecast the future. Harmful Algae 49:68–93. CrossRefGoogle Scholar
  59. Wiltsie D, Schnetzer A, Green J, Borgh MV, Fensin E (2018) Algal blooms and cyanotoxins in Jordan Lake, North Carolina. Toxins (Basel) 10.
  60. Xie X, Basile M, Mash DC (2013) Cerebral uptake and protein incorporation of cyanobacterial toxin β-N-methylamino-L-alanine. Neuroreport 24:779–784. CrossRefGoogle Scholar
  61. Zhou X, Escala W, Papapetropoulos S, Bradley WG, Zhai RG (2009) BMAA neurotoxicity in Drosophila. Amyotroph Lateral Scler 10(Suppl 2):61–66. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Brain Chemistry LabsInstitute for EthnomedicineJacksonUSA
  2. 2.Macquarie University Centre for MND Research, Department of Biological Sciences, Faculty of Medicine and Health SciencesMacquarie UniversitySydneyAustralia

Personalised recommendations