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Neuropathological Mechanisms of β-N-Methylamino-L-Alanine (BMAA) with a Focus on Iron Overload and Ferroptosis

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Abstract

The incidence of neurodegenerative diseases and cyanobacterial blooms is concomitantly increasing worldwide. The cyanotoxin β-N-methylamino-L-alanine (BMAA) is produced by most of the Cyanobacteria spp. This cyanotoxin is described as a potential environmental etiology factor for some sporadic neurodegenerative diseases. Climate change and eutrophication significantly increase the frequency and intensity of cyanobacterial bloom in water bodies. This review evaluates different neuropathological mechanisms of BMAA at molecular and cellular levels and compares the related studies to provide some useful recommendations. Additionally, the structure and properties of BMAA as well as its microbial origin, especially by gut bacteria, are also briefly covered. Unlike previous reviews, we hypothesize the possible neurotoxic mechanism of BMAA through iron overload. We also discuss the involvement of BMAA in excitotoxicity, TAR DNA-binding protein 43 (TDP-43) translocation and accumulation, tauopathy, and other protein misincorporation and misfolding.

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References

  • AAAS (2020) UN to issue first-ever global report on harmful algal blooms. UNESCO Intergovernmental Oceanographic Commission. the American Association for the Advancement of Science (AAAS). https://www.eurekalert.org/pub_releases/2020-11/tca-uti112920.php . Accessed 30 Feb 2021

  • Ahmadi S, Ebralidze II, She Z, Kraatz H-B (2017) Electrochemical studies of tau protein-iron interactions—potential implications for Alzheimer’s disease. Electrochim Acta 236:384–393

    Article  CAS  Google Scholar 

  • Albano R, Lobner DJNr (2018) Transport of BMAA into neurons and astrocytes by system xc. 33(1):1–5

  • Alidadi A, Panahi HKS, Dehhaghi M, Singhania RR, Ghanavati H, Sharafi R, Aghbashlo M, Tabatabaei M, Jouzani GS (2020) Bioethanol production by using plant-pathogenic fungi. In: Fungi in Fuel Biotechnology. Springer, pp 15–38

  • Alkasir R, Li J, Li X, Jin M, Zhu B (2017) Human gut microbiota: the links with dementia development. Protein Cell 8(2):90–102

    Article  CAS  PubMed  Google Scholar 

  • Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351(3):602–611

    Article  CAS  PubMed  Google Scholar 

  • Arif M, Kazim SF, Grundke-Iqbal I, Garruto RM, Iqbal K (2014) Tau pathology involves protein phosphatase 2A in parkinsonism-dementia of Guam. Proc Natl Acad Sci 111(3):1144–1149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arnold ES, Ling S-C, Huelga SC, Lagier-Tourenne C, Polymenidou M, Ditsworth D, Kordasiewicz HB, McAlonis-Downes M, Platoshyn O, Parone PA (2013) ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc Natl Acad Sci 110(8):E736–E745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banack SA, Murch SJ, Cox PA (2006) Neurotoxic flying foxes as dietary items for the Chamorro people, Marianas Islands. J Ethnopharmacol 106(1):97–104

    Article  PubMed  Google Scholar 

  • Banerjee P, Sahoo A, Anand S, Ganguly A, Righi G, Bovicelli P, Saso L, Chakrabarti S (2014) Multiple mechanisms of iron-induced amyloid beta-peptide accumulation in SHSY5Y cells: protective action of negletein. NeuroMol Med 16(4):787–798

    Article  CAS  Google Scholar 

  • Bijur GN, Jope RS (2001) Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3β. J Biol Chem 276(40):37436–37442

    Article  CAS  PubMed  Google Scholar 

  • Boopathi S, Kolandaivel P (2016) Fe2+ binding on amyloid β‐peptide promotes aggregation. Proteins: Structure, Function, and Bioinformatics 84(9):1257–1274

  • Bradley WG, Mash DC (2009) Beyond Guam: the cyanobacteria/BMAA hypothesis of the cause of ALS and other neurodegenerative diseases. Amyotroph Lateral Scler 10(sup2):7–20

    Article  CAS  PubMed  Google Scholar 

  • Brand LE (2009) Human exposure to cyanobacteria and BMAA. Amyotroph Lateral Scler 10(sup2):85–95

    Article  CAS  PubMed  Google Scholar 

  • 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(6):620–635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brenner ED, Stevenson DW, McCombie RW, Katari MS, Rudd SA, Mayer KF, Palenchar PM, Runko SJ, Twigg RW, Dai G (2003) Expressed sequence tag analysis in Cycas, the most primitive living seed plant. Genome Biol 4(12):R78

    Article  PubMed  PubMed Central  Google Scholar 

  • Brettschneider J, Libon DJ, Toledo JB, Xie SX, McCluskey L, Elman L, Geser F, Lee VM-Y, Grossman M, Trojanowski JQ (2012) Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis. Acta Neuropathol 123(3):395–407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buisson A, Choi D (1995) The inhibitory mGluR agonist, S-4-carboxy-3-hydroxy-phenylglycine selectively attenuates NMDA neurotoxicity and oxygen-glucose deprivation-induced neuronal death. Neuropharmacology 34(8):1081–1087

    Article  CAS  PubMed  Google Scholar 

  • Buratti E, Baralle FE (2008) Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci 13(867–7):8

    Google Scholar 

  • Buratti E, Baralle FE (2010) The multiple roles of TDP-43 in pre-mRNA processing and gene expression regulation. RNA Biol 7(4):420–429

    Article  CAS  PubMed  Google Scholar 

  • Carabotti M, Scirocco A, Maselli MA, Severi C (2015) The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Annals of Gastroenterology: Quarterly Publication of the Hellenic Society of Gastroenterology 28(2):203

    Google Scholar 

  • Catherine Q, Susanna W, Isidora E-S, Mark H, Aurelie V, Jean-François H (2013) A review of current knowledge on toxic benthic freshwater cyanobacteria–ecology, toxin production and risk management. Water Res 47(15):5464–5479

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Hambright WS, Na R, Ran Q (2015) Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J Biol Chem 290(47):28097–28106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiu AS, Gehringer MM, Welch JH, Neilan BA (2011) Does α-amino-β-methylaminopropionic acid (BMAA) play a role in neurodegeneration? Int J Environ Res Public Health 8(9):3728–3746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cho J-H, Johnson GV (2003) Glycogen synthase kinase 3β phosphorylates tau at both primed and unprimed sites differential impact on microtubule binding. J Biol Chem 278(1):187–193

    Article  CAS  PubMed  Google Scholar 

  • Cléry A, Blatter M, Allain FH (2008) RNA recognition motifs: boring? Not quite. Curr Opin Struct Biol 18(3):290–298

    Article  PubMed  CAS  Google Scholar 

  • Cox PA, Banack SA, Murch SJ, Rasmussen U, Tien G, Bidigare RR, Metcalf JS, Morrison LF, Codd GA, Bergman B (2005) Diverse taxa of cyanobacteria produce β-N-methylamino-L-alanine, a neurotoxic amino acid. Proc Natl Acad Sci 102(14):5074–5078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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. Proceedings of the Royal Society B: Biological Sciences 283(1823):20152397

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cox PA, Sacks OW (2002) Cycad neurotoxins, consumption of flying foxes, and ALS-PDC disease in Guam. Neurology 58(6):956–959

    Article  PubMed  Google Scholar 

  • Cucchiaroni ML, Viscomi MT, Bernardi G, Molinari M, Guatteo E, Mercuri NB (2010) Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative β-N-methylamino-L-alanine on substantia nigra pars compacta DAergic neurons. J Neurosci 30(15):5176–5188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • D’Amato RJ, Lipman ZP, Snyder SH (1986) Selectivity of the parkinsonian neurotoxin MPTP: toxic metabolite MPP+ binds to neuromelanin. Science 231(4741):987–989

    Article  CAS  PubMed  Google Scholar 

  • Davis DA, Cox PA, Banack SA, Lecusay PD, Garamszegi SP, Hagan MJ, Powell JT, Metcalf JS, Palmour RM, Beierschmitt A (2020) L-serine reduces spinal cord pathology in a vervet model of preclinical ALS/MND. J Neuropathol Exp Neurol 79(4):393–406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davis DA, Garamszegi SP, Banack SA, Dooley PD, Coyne TM, McLean DW, Rotstein DS, Mash DC, Cox PAJT (2021) BMAA, methylmercury, and mechanisms of neurodegeneration in dolphins: a natural model of toxin exposure. 13(10):697

  • Davis DA, Mondo K, Stern E, Annor AK, Murch SJ, Coyne TM, Brand LE, Niemeyer ME, Sharp S, Bradley WG (2019) Cyanobacterial neurotoxin BMAA and brain pathology in stranded dolphins. PLoS One 14 (3):e0213346

  • de Munck E, Munoz-Saez E, Miguel BG, Solas MT, Ojeda I, Martinez 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(2):243–255

    Article  PubMed  CAS  Google Scholar 

  • Dehhaghi M, Kazemi Shariat Panahi H, Braidy N, Guillemin GJ (2020a) Herpetosiphon secondary metabolites inhibit amyloid-β toxicity in human primary astrocytes. J Alzheimers Dis 76(1):423–433

    Article  CAS  PubMed  Google Scholar 

  • Dehhaghi M, Kazemi Shariat Panahi H, Guillemin GJ (2018a) Microorganisms’ footprint in neurodegenerative diseases. Front Cell Neurosci 12:466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dehhaghi M, Kazemi Shariat Panahi H, Guillemin GJ (2019a) Microorganisms, tryptophan metabolism, and kynurenine pathway: a complex interconnected loop influencing human health status. International Journal of Tryptophan Research 12:1178646919852996

    Article  PubMed  PubMed Central  Google Scholar 

  • Dehhaghi M, Kazemi Shariat Panahi H, Holmes EC, Hudson BJ, Schloeffel R, Guillemin GJ (2019b) Human tick-borne diseases in Australia. Front Cell Infect Microbiol 9:3

    Article  PubMed  PubMed Central  Google Scholar 

  • Dehhaghi M, Mohammadipanah F, Guillemin GJ (2018b) Myxobacterial natural products: an under-valued source of products for drug discovery for neurological disorders. Neurotoxicology 66:195–203

    Article  CAS  PubMed  Google Scholar 

  • Dehhaghi M, Panahi HKS, Aghbashlo M, Lam SS, Tabatabaei M (2021) The effects of nano-additives on the performance and emission characteristics of spark-ignition gasoline engines: a critical review with a focus on health impacts. Energy 120259

  • Dehhaghi M, Panahi HKS, Heng B, Guillemin GJ (2020b) The gut microbiota, kynurenine pathway, and immune system interaction in the development of brain cancer. Frontiers in cell and developmental biology 8

  • Dehhaghi M, Panahi HKS, Jouzani GS, Nallusamy S, Gupta VK, Aghbashlo M, Tabatabaei M (2020c) Anaerobic rumen fungi for biofuel production. In: Fungi in Fuel Biotechnology. Springer, pp 149–175

  • Dehhaghi M, Tabatabaei M, Aghbashlo M, Kazemi Shariat Panahi H, Nizami A-S (2019c) A state-of-the-art review on the application of nanomaterials for enhancing biogas production. J Environ Manage 251:109597

  • Dehhaghi M, Tan V, Heng B, Braidy N, Mohammadipanah F, Guillemin GJ (2019d) Neuroprotective effect of myxobacterial extracts on quinolinic acid-induced toxicity in primary human neurons. Neurotox Res 35(2):281–290

    Article  CAS  PubMed  Google Scholar 

  • Dehhaghi M, Tan V, Heng B, Mohammadipanah F, Guillemin GJ (2019e) Protective effects of myxobacterial extracts on hydrogen peroxide-induced toxicity on human primary astrocytes. Neuroscience 399:1–11

    Article  CAS  PubMed  Google Scholar 

  • 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 10(1):6

    Article  CAS  Google Scholar 

  • Dexter D, Wells F, Lee A, Agid F, Agid Y, Jenner P, Marsden C (1989) Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J Neurochem 52(6):1830–1836

    Article  CAS  PubMed  Google Scholar 

  • Dill J, Wang H, Zhou F, Li S (2008) Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS. J Neurosci 28(36):8914–8928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doble A (1999) The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther 81(3):163–221

    Article  CAS  PubMed  Google Scholar 

  • Doucette WJ (2000) Soil and sediment sorption coefficients. CRC Press LLC, Boca Raton, Florida

    Book  Google Scholar 

  • Downing S, Downing TG (2016) The metabolism of the non-proteinogenic amino acid β-N-methylamino-L-alanine (BMAA) in the cyanobacterium synechocystis PCC6803. Toxicon 115:41–48

    Article  CAS  PubMed  Google Scholar 

  • Duncan MW, Markey SP, Weick BG, Pearson PG, Ziffer H, Hu Y, Kopin IJ (1992) 2-Amino-3-(methylamino) propanoic acid (BMAA) bioavailability in the primate. Neurobiol Aging 13(2):333–337

    Article  CAS  PubMed  Google Scholar 

  • Duncan MW, Villacreses NE, Pearson PG, Wyatt L, Rapoport SI, Kopin IJ, Markey SP, Smith QR (1991) 2-amino-3-(methylamino)-propanoic acid (BMAA) pharmacokinetics and blood-brain barrier permeability in the rat. J Pharmacol Exp Ther 258(1):27–35

    CAS  PubMed  Google 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 8 (9):e75376

  • Dunlop RA, Guillemin GJ (2019a) 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. J Neurotoxicity Research 36(3):602–611

    Article  Google Scholar 

  • Dunlop RA, Guillemin GJ (2019b) 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. Neurotoxicity research 1–10

  • Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA (2005) Diversity of the human intestinal microbial flora. Science 308(5728):1635–1638

    Article  PubMed  PubMed Central  Google Scholar 

  • Engel T, Goñi-Oliver P, Lucas JJ, Avila J, Hernández F (2006a) Chronic lithium administration to FTDP-17 tau and GSK-3β overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. J Neurochem 99(6):1445–1455

    Article  CAS  PubMed  Google Scholar 

  • Engel T, Lucas JJ, Gómez-Ramos P, Moran MA, Ávila J, Hernández F (2006b) Cooexpression of FTDP-17 tau and GSK-3β in transgenic mice induce tau polymerization and neurodegeneration. Neurobiol Aging 27(9):1258–1268

    Article  CAS  PubMed  Google Scholar 

  • Faassen EJ, Antoniou MG, Beekman-Lukassen W, Blahova L, Chernova E, Christophoridis C, Combes A, Edwards C, Fastner J, Harmsen J (2016) A collaborative evaluation of LC-MS/MS based methods for BMAA analysis: soluble bound BMAA found to be an important fraction. Mar Drugs 14(3):45

    Article  PubMed Central  CAS  Google Scholar 

  • Fichtner M, Voigt K, Schuster S (2017) The tip and hidden part of the iceberg: proteinogenic and non-proteinogenic aliphatic amino acids. Biochimica et Biophysica Acta (BBA)-General Subjects 1861(1):3258–3269

  • Friedlich A, Tanzi R, Rogers J (2007) The 5′-untranslated region of Parkinson’s disease α-synuclein messenger RNA contains a predicted iron responsive element. Mol Psychiatry 12(3):222–223

    Article  CAS  PubMed  Google Scholar 

  • Galante D, Cavallo E, Perico A, D'Arrigo C (2018) Effect of ferric citrate on amyloid‐beta peptides behavior. Biopolymers 109(6):e23224

  • Gao J, Wang L, Huntley ML, Perry G, Wang X (2018) Pathomechanisms of TDP-43 in neurodegeneration. J Neurochem 146(1):7–20

    Article  CAS  Google Scholar 

  • Genazzani A, Casabona G, L’Episcopo M, Condorelli D, Dell’Albani P, Shinozaki H, Nicoletti F (1993) Characterization of metabotropic glutamate receptors negatively linked to adenylyl cyclase in brain slices. Brain Res 622(1–2):132–138

    Article  CAS  PubMed  Google Scholar 

  • Goedert M, Spillantini M, Potier M, Ulrich J, Crowther R (1989) Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J 8(2):393–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodman L (1953) Alzheimer’s disease: a clinico-pathologic analysis of twenty-three cases with a theory on pathogenesis. J Nerv Ment Dis 118(2):97–130

    Article  CAS  PubMed  Google Scholar 

  • Guo C, Wang P, Zhong M-L, Wang T, Huang X-S, Li J-Y, Wang Z-Y (2013) Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain. Neurochem Int 62(2):165–172

    Article  CAS  PubMed  Google Scholar 

  • Hambright WS, Fonseca RS, Chen L, Na R, Ran Q (2017) Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol 12:8–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han N-C, Bullwinkle TJ, Loeb KF, Faull KF, Mohler K, Rinehart J, Ibba M (2020) The mechanism of β-N-methylamino-l-alanine inhibition of tRNA aminoacylation and its impact on misincorporation. J Biol Chem 295(5):1402–1410

    Article  PubMed  Google Scholar 

  • Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441(7095):885–889

    Article  CAS  PubMed  Google Scholar 

  • Hardy J, Singleton A (2008) The HapMap: charting a course for genetic discovery in neurological diseases. Arch Neurol 65(3):319–321

    Article  PubMed  Google Scholar 

  • Huisman J, Codd GA, Paerl HW, Ibelings BW, Verspagen JM, Visser PM (2018) Cyanobacterial blooms. Nat Rev Microbiol 16(8):471–483

    Article  CAS  PubMed  Google Scholar 

  • Iqbal K, Gong C-X, Liu F (2014) Microtubule-associated protein tau as a therapeutic target in Alzheimer’s disease. Expert Opin Ther Targets 18(3):307–318

    Article  CAS  PubMed  Google Scholar 

  • Iturriaga R, Mitchell B (1986) Chroococcoid cyanobacteria: a significant component in the food web dynamics of the open ocean. Mar Ecol Prog Ser 28(3):291–297

    Article  Google Scholar 

  • Jacobs KR, Lim CK, Blennow K, Zetterberg H, Chatterjee P, Martins RN, Brew BJ, Guillemin GJ, Lovejoy DB (2019) Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer’s disease and relationship to amyloid-β and tau. Neurobiol Aging 80:11–20

    Article  CAS  PubMed  Google Scholar 

  • Jarrett JT, Lansbury PT Jr (1993) Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 73(6):1055–1058

    Article  CAS  PubMed  Google Scholar 

  • Jenner P, Schapira A, Marsden C (1992) New insights into the cause of Parkinson’s disease. Neurology 42(12):2241–2241

    Article  CAS  PubMed  Google Scholar 

  • Jiang L, Aigret B, De Borggraeve WM, Spacil Z, Ilag LL (2012) Selective LC-MS/MS method for the identification of BMAA from its isomers in biological samples. Anal Bioanal Chem 403(6):1719–1730

    Article  CAS  PubMed  Google Scholar 

  • Jiang L, Eriksson J, Lage S, Jonasson S, Shams S, Mehine M, Ilag LL, Rasmussen U (2014) Diatoms: a novel source for the neurotoxin BMAA in aquatic environments. PLoS One 9(1):e84578

  • Josephs KA, Murray ME, Whitwell JL, Tosakulwong N, Weigand SD, Petrucelli L, Liesinger AM, Petersen RC, Parisi JE, Dickson DW (2016) Updated TDP-43 in Alzheimer’s disease staging scheme. Acta Neuropathol 131(4):571–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karlsson O, Berg A-L, Hanrieder J, Arnerup 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(3):423–436

    Article  CAS  PubMed  Google Scholar 

  • Karlsson O, Roman E, Berg A-L, Brittebo EB (2011) Early hippocampal cell death, and late learning and memory deficits in rats exposed to the environmental toxin BMAA (β-N-methylamino-L-alanine) during the neonatal period. Behav Brain Res 219(2):310–320

    Article  CAS  PubMed  Google Scholar 

  • Kazemi Shariat Panahi H, Dehhaghi M, Aghbashlo M, Karimi K, Tabatabaei M (2019a) Conversion of residues from agro-food industry into bioethanol in Iran: an under-valued biofuel additive to phase out MTBE in gasoline. Renewable Energy 145:699–710

    Article  CAS  Google Scholar 

  • Kazemi Shariat Panahi H, Dehhaghi M, Aghbashlo M, Karimi K, Tabatabaei M (2019b) Shifting fuel feedstock from oil wells to sea: Iran outlook and potential for biofuel production from brown macroalgae (ochrophyta; phaeophyceae). Renewable Sustainable Energy Rev 112:626–642

    Article  Google Scholar 

  • Kazemi Shariat Panahi H, Dehhaghi M, Kinder JE, Ezeji TC (2019c) A review on green liquid fuels for the transportation sector: a prospect of microbial solutions to climate change. Biofuel Res J 23:995–1024

    Article  Google Scholar 

  • 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 10(2):83

    Article  PubMed Central  CAS  Google Scholar 

  • Lane DJ, Ayton S, Bush AI (2018) Iron and Alzheimer’s disease: an update on emerging mechanisms. J Alzheimers Dis 64(s1):S379–S395

    Article  CAS  PubMed  Google Scholar 

  • Langston J, Forno L, Tetrud J, Reeves A, Kaplan J, Karluk D (1999) Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine exposure. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 46(4):598–605

    Article  CAS  Google Scholar 

  • Laugeray A, Oummadi A, Jourdain C, Feat J, Meyer-Dilhet G, Menuet A, Plé K, Gay M, Routier S, Mortaud S (2018) Perinatal exposure to the cyanotoxin β-N-méthylamino-l-alanine (BMAA) results in long-lasting behavioral changes in offspring—potential involvement of DNA damage and oxidative stress. Neurotox Res 33(1):87–112

    Article  CAS  PubMed  Google Scholar 

  • 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(7107):50–55

    Article  CAS  PubMed  Google Scholar 

  • Lehotzky A, Tirián L, Tökési N, Lénárt P, Szabó B, Kovács J, Ovádi J (2004) Dynamic targeting of microtubules by TPPP/p25 affects cell survival. J Cell Sci 117(25):6249–6259

    Article  CAS  PubMed  Google Scholar 

  • Lei P, Ayton S, Bush AI, Adlard PA (2011) GSK-3 in neurodegenerative diseases. International Journal of Alzheimer’s Disease 2011

  • Leroy K, Menu R, Conreur J, Dayanandan R, Lovestone S, Anderton B, Brion JP (2000) The function of the microtubule-associated protein tau is variably modulated by graded changes in glycogen synthase kinase-3β activity. FEBS Lett 465(1):34–38

    Article  CAS  PubMed  Google Scholar 

  • Levin J, Högen T, Hillmer AS, Bader B, Schmidt F, Kamp F, Kretzschmar HA, Bötzel K, Giese A (2011) Generation of ferric iron links oxidative stress to α-synuclein oligomer formation. J Parkinsons Dis 1(2):205–216

    Article  CAS  PubMed  Google Scholar 

  • Li B, Castano AP, Hudson TE, Nowlin BT, Lin S-L, Bonventre JV, Swanson KD, Duffield JS (2010) The melanoma-associated transmembrane glycoprotein Gpnmb controls trafficking of cellular debris for degradation and is essential for tissue repair. FASEB J 24(12):4767–4781

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Cao F, Yin H-l, Huang Z-j, Lin Z-t, Mao N, Sun B, Wang G (2020) Ferroptosis: past, present and future. Cell Death Dis 11(2):1–13

    Article  PubMed  PubMed Central  Google Scholar 

  • Lindström H, Luthman J, Mouton P, Spencer P, Olson L (1990) Plant-derived neurotoxic amino acids (β-N-oxalylamino-l-alanine and β-N-methylamino-l-alanine): effects on central monoamine neurons. J Neurochem 55(3):941–949

    Article  PubMed  Google Scholar 

  • Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2005) Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci 22(8):1942–1950

    Article  PubMed  Google Scholar 

  • Liu X, Rush T, Zapata J, Lobner D (2009) β-N-methylamino-l-alanine induces oxidative stress and glutamate release through action on system Xc−. Exp Neurol 217(2):429–433

    Article  CAS  PubMed  Google Scholar 

  • Lobner D (2009) Mechanisms of β-N-methylamino-L-alanine induced neurotoxicity. Amyotroph Lateral Scler 10(sup2):56–60

    Article  CAS  PubMed  Google Scholar 

  • Lobner D, Piana PMT, Salous AK, Peoples RW (2007) β-N-methylamino-L-alanine enhances neurotoxicity through multiple mechanisms. Neurobiol Dis 25(2):360–366

    Article  CAS  PubMed  Google Scholar 

  • Lopicic S, Nedeljkov V, Cemerikic D (2009) Augmentation and ionic mechanism of effect of β-N-methylamino-L-alanine in presence of bicarbonate on membrane potential of Retzius nerve cells of the leech Haemopis sanguisuga. Comp Biochem Physiol a: Mol Integr Physiol 153(3):284–292

    Article  CAS  Google Scholar 

  • Lu Y, Prudent M, Fauvet B, Lashuel HA, Girault HH (2011) Phosphorylation of α-synuclein at Y125 and S129 alters its metal binding properties: implications for understanding the role of α-synuclein in the pathogenesis of Parkinson’s disease and related disorders. ACS Chem Neurosci 2(11):667–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ly PT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, Zhang M, Yang Y, Cai F, Woodgett J (2012) Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. The Journal of clinical investigation 123 (1)

  • Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Ravits J, Stewart H (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 61(5):427–434

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Mandelkow E-M, Mandelkow E (2012) Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harbor perspectives in medicine 2(7):a006247

  • Manichanh C, Borruel N, Casellas F, Guarner F (2012) The gut microbiota in IBD. Nat Rev Gastroenterol Hepatol 9(10):599

    Article  CAS  PubMed  Google Scholar 

  • Martin-Bastida A, Pietracupa S, Piccini P (2017) Neuromelanin in Parkinsonian disorders: an update. Int J Neurosci 127(12):1116–1123

    Article  CAS  PubMed  Google Scholar 

  • Mastroberardino PG, Hoffman EK, Horowitz MP, Betarbet R, Taylor G, Cheng D, Na HM, Gutekunst C-A, Gearing M, Trojanowski JQJNod (2009) A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease 34(3):417–431

  • Mohammadipanah F, Panahi HKS, Imanparast F, Hamedi J (2016) Development of a reversed-phase liquid chromatographic assay for the quantification of total persipeptides in fermentation broth. Chromatographia 79(19–20):1325–1332

    Article  CAS  Google Scholar 

  • Monteiro M, Costa M, Moreira C, Vasconcelos VM, Baptista MS (2017) Screening of BMAA-producing cyanobacteria in cultured isolates and in in situ blooms. J Appl Phycol 29(2):879–888

    Article  CAS  Google Scholar 

  • Mukrasch MD, Bibow S, Korukottu J, Jeganathan S, Biernat J, Griesinger C, Mandelkow E, Zweckstetter M (2009) Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biology 7 (2)

  • Muñoz-Saez E, de Munck E, Arahuetes RM, Solas MT, Martínez AM, Miguel BG (2013) β-N-methylamino-L-alanine induces changes in both GSK3 and TDP-43 in human neuroblastoma. J Toxicol Sci 38(3):425–430

    Article  PubMed  Google Scholar 

  • Muñoz-Sáez E, de Munck GE, Portero RMA, Martínez A, Alados MTS, Miguel BG (2015) Analysis of β-N-methylamino-L-alanine (L-BMAA) neurotoxicity in rat cerebellum. Neurotoxicology 48:192–205

    Article  PubMed  CAS  Google Scholar 

  • Murch S, Cox P, Banack S, Steele J, Sacks O (2004) Occurrence of β-methylamino-l-alanine (BMAA) in ALS/PDC patients from Guam. Acta Neurol Scand 110(4):267–269

    Article  CAS  PubMed  Google Scholar 

  • Myers TG, Nelson S (1990) Neuroactive carbamate adducts of beta-N-methylamino-L-alanine and ethylenediamine. Detection and quantitation under physiological conditions by 13C NMR. Journal of Biological Chemistry 265(18):10193–10195

  • Mylonas E, Hascher A, Bernado P, Blackledge M, Mandelkow E, Svergun DI (2008) Domain conformation of tau protein studied by solution small-angle X-ray scattering. Biochemistry 47(39):10345–10353

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Lipton S (2011) Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases. Cell Death Differ 18(9):1478–1486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ndayisaba A, Kaindlstorfer C, Wenning GK (2019) Iron in neurodegeneration–cause or consequence? Frontiers in Neuroscience 13

  • Nedeljkov V, LOPIČIĆ S, Pavlović D, Čemerikić D, (2005) Electrophysiological effect of β-N-methylamino-L-alanine on Retzius nerve cells of the leech Haemopis sanguisuga. Ann N Y Acad Sci 1048(1):349–351

    Article  CAS  PubMed  Google Scholar 

  • Neve RL, Harris P, Kosik KS, Kurnit DM, Donlon TA (1986) Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. Mol Brain Res 1(3):271–280

    Article  CAS  Google Scholar 

  • Nunes-Costa D, Magalhães JD, Cardoso SM, Empadinhas N (2020) Microbial BMAA and the pathway for Parkinson’s disease neurodegeneration. Frontiers in Aging Neuroscience 12:26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nunn PB, Bell EA, Watson AA, Nash RJ (2010) Toxicity of non-protein amino acids to humans and domestic animals. Natural product communications 5(3):1934578X1000500329

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Nunn PB, Codd GAJTR (2019) Environmental distribution of the neurotoxin L-BMAA in Paenibacillus species. 8(6):781–783

  • Nunn PB, O’Brien P (1989) The interaction of β-N-methylamino-L-alanine with bicarbonate: an 1H-NMR study. FEBS Lett 251(1–2):31–35

    Article  CAS  PubMed  Google Scholar 

  • Okle O, Stemmer K, Deschl U, Dietrich DR (2013) L-BMAA induced ER stress and enhanced caspase 12 cleavage in human neuroblastoma SH-SY5Y cells at low nonexcitotoxic concentrations. toxicological sciences 131(1):217–224

  • Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B (2000) The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 20(16):6048–6054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oueslati A (2016) Implication of alpha-synuclein phosphorylation at S129 in synucleinopathies: what have we learned in the last decade? J Parkinsons Dis 6(1):39–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oueslati A, Paleologou KE, Schneider BL, Aebischer P, Lashuel HA (2012) Mimicking phosphorylation at serine 87 inhibits the aggregation of human α-synuclein and protects against its toxicity in a rat model of Parkinson’s disease. J Neurosci 32(5):1536–1544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pablo J, Banack S, Cox P, Johnson T, Papapetropoulos S, Bradley WG, Buck A, Mash DC (2009) Cyanobacterial neurotoxin BMAA in ALS and Alzheimer’s disease. Acta Neurol Scand 120(4):216–225

    Article  CAS  PubMed  Google Scholar 

  • Panahi HKS, Dehhaghi M, Lam SS, Peng W, Aghbashlo M, Tabatabaei M, Guillemin GJ Oncolytic viruses as a promising therapeutic strategy against the detrimental health impacts of air pollution: the case of glioblastoma multiforme. In: Seminars in cancer biology, 2021. Elsevier

  • Panahi HKS, Dehhaghi M, Ok YS, Nizami A-S, Khoshnevisan B, Mussatto SI, Aghbashlo M, Tabatabaei M, Lam SS (2020) A comprehensive review of engineered biochar: production, characteristics, and environmental applications. J Clean Prod 270:122462

  • Peng Y, Wang C, Xu HH, Liu Y-N, Zhou F (2010) Binding of α-synuclein with Fe (III) and with Fe (II) and biological implications of the resultant complexes. J Inorg Biochem 104(4):365–370

    Article  CAS  PubMed  Google Scholar 

  • Percival SL, Williams DW (2014) Cyanobacteria. In: Microbiology of Waterborne Diseases. Elsevier, pp 79–88

  • Peters DG, Pollack AN, Cheng KC, Sun D, Saido T, Haaf MP, Yang QX, Connor JR, Meadowcroft MD (2018) Dietary lipophilic iron alters amyloidogenesis and microglial morphology in Alzheimer’s disease knock-in APP mice. Metallomics 10(3):426–443

    Article  CAS  PubMed  Google Scholar 

  • Popova AA, Rasmussen U, Semashko TA, Govorun VM, Koksharova OA (2018) Stress effects of cyanotoxin β-methylamino-L-alanine (BMAA) on cyanobacterial heterocyst formation and functionality. Environmental Microbiology Reports 10(3):369–377

    Article  CAS  PubMed  Google Scholar 

  • Prema A, Justin Thenmozhi A, Manivasagam T, Mohamed Essa M, Guillemin GJ (2017) Fenugreek seed powder attenuated aluminum chloride-induced tau pathology, oxidative stress, and inflammation in a rat model of Alzheimer’s disease. J Alzheimers Dis 60(s1):S209–S220

    Article  CAS  PubMed  Google Scholar 

  • PubChem (2013a) 3-(methylamino)-(dl)-alanine (annotation). U.S. National Library of Medicine, National Center for Biotechnology Information. https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3461. Accessed 04 March 2020

  • PubChem (2013b) 3-(methylamino)-(dl)-alanine (annotation). Hazardous Substances Data Bank (HSDB). U.S. National Library of Medicine, National Center for Biotechnology Information. https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3461. Accessed 04 March 2020

  • Quinn AW, Phillips CR, Violi JP, Steele JR, Johnson MS, Westerhausen MT, Rodgers KJ (2021) β-Methylamino-L-alanine-induced protein aggregation in vitro and protection by L-serine. Amino Acids 1–9

  • Rao SD, Banack SA, Cox PA, Weiss JH (2006) BMAA selectively injures motor neurons via AMPA/kainate receptor activation. Exp Neurol 201(1):244–252

    Article  CAS  PubMed  Google Scholar 

  • Rather MA, Justin-Thenmozhi A, Manivasagam T, Saravanababu C, Guillemin GJ, Essa MM (2019) Asiatic acid attenuated aluminum chloride-induced tau pathology, oxidative stress and apoptosis via AKT/GSK-3β signaling pathway in Wistar rats. Neurotox Res 35(4):955–968

    Article  CAS  Google Scholar 

  • Réveillon D, Abadie E, Séchet V, Brient L, Savar V, Bardouil M, Hess P, Amzil Z (2014) Beta-N-methylamino-L-alanine: LC-MS/MS optimization, screening of cyanobacterial strains and occurrence in shellfish from Thau, a French Mediterranean lagoon. Mar Drugs 12(11):5441–5467

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rockenstein E, Torrance M, Adame A, Mante M, Bar-On P, Rose JB, Crews L, Masliah E (2007) Neuroprotective effects of regulators of the glycogen synthase kinase-3β signaling pathway in a transgenic model of Alzheimer’s disease are associated with reduced amyloid precursor protein phosphorylation. J Neurosci 27(8):1981–1991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ross SM, Seelig M, Spencer PS (1987) Specific antagonism of excitotoxic action of ‘uncommon’amino acids assayed in organotypic mouse cortical cultures. Brain Res 425(1):120–127

    Article  CAS  PubMed  Google Scholar 

  • Sajedi H, Mohammadipanah F, Shariat Panahi HK (2018) An image analysis-aided method for redundancy reduction in differentiation of identical Actinobacterial strains. Future Microbiol 13(3):313–329

    Article  CAS  PubMed  Google Scholar 

  • Samardzic K, Steele JR, Violi JP, Colville A, Mitrovic SM, Rodgers KJ (2021) Toxicity and bioaccumulation of two non-protein amino acids synthesised by cyanobacteria, β-N-methylamino-L-alanine (BMAA) and 2, 4-diaminobutyric acid (DAB), on a crop plant. Ecotoxicology and Environmental Safety 208:111515

  • Sang H, Lu Z, Li Y, Ru B, Wang W, Chen J (2001) Phosphorylation of tau by glycogen synthase kinase 3β in intact mammalian cells influences the stability of microtubules. Neurosci Lett 312(3):141–144

    Article  CAS  PubMed  Google Scholar 

  • Schneider T, Simpson C, Desai P, Tucker M, Lobner D (2020) Neurotoxicity of isomers of the environmental toxin L-BMAA. Toxicon 184:175–179

    Article  CAS  PubMed  Google Scholar 

  • Scott L, Downing S, Phelan R, Downing T (2014) Environmental modulation of microcystin and β-N-methylamino-L-alanine as a function of nitrogen availability. Toxicon 87:1–5

    Article  CAS  PubMed  Google Scholar 

  • Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Rådmark O, Wurst W (2008) Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent-and AIF-mediated cell death. Cell Metab 8(3):237–248

    Article  CAS  PubMed  Google Scholar 

  • Sekirov I, Russell SL, Antunes LCM, Finlay BB (2010) Gut microbiota in health and disease. Physiol Rev 90(3):859–904

    Article  CAS  PubMed  Google Scholar 

  • Shirzad M, Kazemi Shariat Panahi H, Dashtic BB, Rajaeifard MA, Aghbashlo M, Tabatabaei M (2019) A comprehensive review on electricity generation and GHG emission reduction potentials through anaerobic digestion of agricultural and livestock/slaughterhouse wastes in Iran. Renewable Sustainable Energy Rev 111:571–594

    Article  CAS  Google Scholar 

  • Silva DF, Candeias E, Esteves AR, Magalhães JD, Ferreira IL, Nunes-Costa D, Rego AC, Empadinhas N, Cardoso SM (2020) Microbial BMAA elicits mitochondrial dysfunction, innate immunity activation, and Alzheimer’s disease features in cortical neurons. J Neuroinflammation 17(1):1–18

    Article  CAS  Google Scholar 

  • Silvestri L, Camaschella C (2008) A potential pathogenetic role of iron in Alzheimer’s disease. J Cell Mol Med 12(5a):1548–1550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sloan SA, Barres BA (2013) Glia as primary drivers of neuropathology in TDP-43 proteinopathies. Proc Natl Acad Sci 110(12):4439–4440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(4814):517–522

    Article  CAS  PubMed  Google Scholar 

  • Swann R, Laskowski D, McCall P, Vander Kuy K, Dishburger H (1983) A rapid method for the estimation of the environmental parameters octanol/water partition coefficient, soil sorption constant, water to air ratio, and water solubility. In: Residue Reviews. Springer, pp 17–28

  • Tabatabaei M, Alidadi A, Dehhaghi M, Panahi HKS, Lam SS, Nizami A-S, Aghbashlo M, Jouzani GS (2020) Fungi as bioreactors for biodiesel production. In: Fungi in Fuel Biotechnology. Springer, pp 39–67

  • Tahmasebinia F, Emadi S (2017) Effect of metal chelators on the aggregation of beta-amyloid peptides in the presence of copper and iron. Biometals 30(2):285–293

    Article  CAS  PubMed  Google Scholar 

  • Tan VX, Lassus B, Lim CK, Tixador P, Courte J, Bessede A, Guillemin GJ, Peyrin J-M (2018a) Neurotoxicity of the cyanotoxin BMAA through axonal degeneration and intercellular spreading. Neurotox Res 33(1):62–75

    Article  CAS  PubMed  Google Scholar 

  • Tan VX, Mazzocco C, Varney B, Bodet D, Guillemin TA, Bessede A, Guillemin GJ (2018b) Detection of the cyanotoxins L-BMAA uptake and accumulation in primary neurons and astrocytes. Neurotox Res 33(1):55–61

    Article  CAS  PubMed  Google Scholar 

  • Tedeschi V, Petrozziello T, Sisalli MJ, Boscia F, Canzoniero LMT, Secondo A (2019) The activation of Mucolipin TRP channel 1 (TRPML1) protects motor neurons from L-BMAA neurotoxicity by promoting autophagic clearance. Sci Rep 9(1):1–11

    Article  CAS  Google Scholar 

  • Tian K-W, Jiang H, Wang B-B, Zhang F, Han S (2016) Intravenous injection of L-BMAA induces a rat model with comprehensive characteristics of amyotrophic lateral sclerosis/Parkinson–dementia complex. Toxicology Research 5(1):79–96

    Article  PubMed  Google Scholar 

  • Tripathi A, Gottesman S (2016) Phosphate on, rubbish out. Nature 539(7627):38–39

    Article  CAS  PubMed  Google Scholar 

  • Ursini F, Bindoli A (1987) The role of selenium peroxidases in the protection against oxidative damage of membranes. Chem Phys Lipid 44(2–4):255–276

    Article  CAS  Google Scholar 

  • Valdes AM, Walter J, Segal E, Spector TD (2018) Role of the gut microbiota in nutrition and health. Bmj 361:k2179

  • van Onselen R, Downing TG (2019) β-N-methylamino-L-alanine inhibits human catalase activity: possible implications for neurodegenerative disease development. Int J Toxicol 38(2):129–134

    Article  PubMed  CAS  Google Scholar 

  • Vega A, Bell E (1967) α-Amino-β-methylaminopropionic acid, a new amino acid from seeds of Cycas circinalis. Phytochemistry 6(5):759–762

    Article  CAS  Google Scholar 

  • Violi JP, Facey JA, Mitrovic SM, Colville A, Rodgers KJ (2019a) Production of β-methylamino-L-alanine (BMAA) and its isomers by freshwater diatoms. Toxins 11(9):512

    Article  CAS  PubMed Central  Google Scholar 

  • Violi JP, Mitrovic SM, Colville A, Main BJ, Rodgers KJ (2019b) Prevalence of β-methylamino-L-alanine (BMAA) and its isomers in freshwater cyanobacteria isolated from eastern Australia. Ecotoxicol Environ Saf 172:72–81

    Article  CAS  PubMed  Google Scholar 

  • Visser PM, Verspagen JM, Sandrini G, Stal LJ, Matthijs HC, Davis TW, Paerl HW, Huisman J (2016) How rising CO2 and global warming may stimulate harmful cyanobacterial blooms. Harmful Algae 54:145–159

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Yan C, Qiu J, Liu C, Yan Y, Ji Y, Wang G, Chen H, Li Y, Li A (2021) Food web biomagnification of the neurotoxin β-N-methylamino-L-alanine in a diatom-dominated marine ecosystem in China. Journal of Hazardous Materials 404:124217

  • Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L (2014) The role of iron in brain ageing and neurodegenerative disorders. The Lancet Neurology 13(10):1045–1060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weiss JH, Choi DW (1988) Beta-N-methylamino-L-alanine neurotoxicity: requirement for bicarbonate as a cofactor. Science 241(4868):973–975

    Article  CAS  PubMed  Google Scholar 

  • Weiss JH, Koh J-y, Choi DW (1989) Neurotoxicity ofβ-N-methylamino-l-alanine (BMAA) andβ-N-oxalylamino-l-alamine (BOAA) on cultured cortical neurons. Brain Res 497(1):64–71

    Article  CAS  PubMed  Google Scholar 

  • Whitton BA (2012) Ecology of cyanobacteria II: their diversity in space and time. Springer Science & Business Media

  • Wilms H, Zecca L, Rosenstiel P, Sievers J, Deuschl G, Lucius R (2007) Inflammation in Parkinson’s diseases and other neurodegenerative diseases: cause and therapeutic implications. Curr Pharm Des 13(18):1925–1928

    Article  CAS  PubMed  Google Scholar 

  • Wilson KM, Burkus-Matesevac A, Maddox SW, Chouinard CD (2021) Native ubiquitin structural changes resulting from complexation with β-methylamino-L-alanine (BMAA). J Am Soc Mass Spectrom 32(4):895–900

    Article  CAS  PubMed  Google Scholar 

  • Wong BX, Tsatsanis A, Lim LQ, Adlard PA, Bush AI, Duce JA (2014) β-Amyloid precursor protein does not possess ferroxidase activity but does stabilize the cell surface ferrous iron exporter ferroportin. PLoS One 9(12)

  • Xie L, Zheng W, Xin N, Xie J-W, Wang T, Wang Z-Y (2012) Ebselen inhibits iron-induced tau phosphorylation by attenuating DMT1 up-regulation and cellular iron uptake. Neurochem Int 61(3):334–340

    Article  CAS  PubMed  Google Scholar 

  • Xie X, Basile M, Mash DC (2013) Cerebral uptake and protein incorporation of cyanobacterial toxin β-N-methylamino-L-alanine. NeuroReport 24(14):779–784

    Article  CAS  PubMed  Google Scholar 

  • Yin HZ, Yu S, Hsu C-I, Liu J, Acab A, Wu R, Tao A, Chiang BJ, Weiss JH (2014) Intrathecal infusion of BMAA induces selective motor neuron damage and astrogliosis in the ventral horn of the spinal cord. Exp Neurol 261:1–9

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y-J, Xu Y-F, Cook C, Gendron TF, Roettges P, Link CD, Lin W-L, Tong J, Castanedes-Casey M, Ash P (2009) Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci 106(18):7607–7612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y-J, Xu Y-f, Dickey CA, Buratti E, Baralle F, Bailey R, Pickering-Brown S, Dickson D, Petrucelli L (2007) Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. J Neurosci 27(39):10530–10534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Whalen JK (2019) Production of the neurotoxin beta-N-methylamino-l-alanine may be triggered by agricultural nutrients: an emerging public health issue. Water Research 115335

  • Zhou ZD, Tan E-K (2017) Iron regulatory protein (IRP)-iron responsive element (IRE) signaling pathway in human neurodegenerative diseases. Mol Neurodegener 12(1):75

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zucca FA, Segura-Aguilar J, Ferrari E, Muñoz P, Paris I, Sulzer D, Sarna T, Casella L, Zecca L (2017) Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Prog Neurobiol 155:96–119

    Article  CAS  PubMed  Google Scholar 

  • Zucca FA, Vanna R, Cupaioli FA, Bellei C, De Palma A, Di Silvestre D, Mauri P, Grassi S, Prinetti A, Casella L (2018a) Neuromelanin organelles are specialized autolysosomes that accumulate undegraded proteins and lipids in aging human brain and are likely involved in Parkinson’s disease. NPJ Parkinson's Dis 4(1):1–23

  • Zucca FA, Vanna R, Cupaioli FA, Bellei C, De Palma A, Di Silvestre D, Mauri P, Grassi S, Prinetti A, Casella L (2018b) Neuromelanin organelles are specialized autolysosomes that accumulate undegraded proteins and lipids in aging human brain and are likely involved in Parkinson’s disease. NPJ Parkinson’s Disease 4(1):1–23

    Article  CAS  Google Scholar 

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Funding

MD and HK are supported by international scholarships from Macquarie University. GJG Guillemin is funded by the National Health and Medical Research Council (NHMRC) PP1176660, PANDIS.org, The Handbury Foundation, and Macquarie University. The cyanotoxin research project has been originally supported by the Australian Research Council (ARC) grant DP160105005 and is currently funded by Ms. Rosemary Pryor’s philanthropic support.

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Authors and Affiliations

  1. Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia

    Hamed Kazemi Shariat Panahi, Mona Dehhaghi, Benjamin Heng, Gilles J. Guillemin & Vanessa X. Tan

  2. PANDIS.Org, Bendigo, Australia

    Mona Dehhaghi, Gilles J. Guillemin & Vanessa X. Tan

  3. Department of Microbial Biotechnology, School of Biology and Centre of Excellence in Phylogeny of Living Organisms, College of Science, University of Tehran, Tehran, Iran

    Mona Dehhaghi

  4. Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia

    Darius J. R. Lane & Ashley I. Bush

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  1. Hamed Kazemi Shariat Panahi
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HKSP and MD wrote the manuscript and prepared the figures. BH, DJR, AIB, VT, and GJG read and edited the manuscript. GJG and VT are co-senior authors.

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Correspondence to Gilles J. Guillemin.

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Kazemi Shariat Panahi, H., Dehhaghi, M., Heng, B. et al. Neuropathological Mechanisms of β-N-Methylamino-L-Alanine (BMAA) with a Focus on Iron Overload and Ferroptosis. Neurotox Res 40, 614–635 (2022). https://doi.org/10.1007/s12640-021-00455-6

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