The neurotoxic non-protein amino acid, β-N-methylamino-L-alanine (BMAA), was first associated with the high incidence of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) in Guam. Recently, BMAA has been implicated as a fierce environmental factor that contributes to the etiology of Alzheimer’s and Parkinson’s diseases, in addition to ALS. However, the toxicity of BMAA in vivo has not been clearly demonstrated. Here we report our investigation of the neurotoxicity of BMAA in Drosophila. We found that dietary intake of BMAA reduced life span, locomotor functions, and learning and memory abilities in flies. The severity of the alterations in phenotype is correlated with the concentration of BMAA detected in flies. Interestingly, developmental exposure to BMAA had limited impact on survival rate, but reduced fertility in females, and caused delayed neurological impairment in aged adults. Our studies indicate that BMAA exposure causes chronic neurotoxicity, and that Drosophila serves as a useful model in dissecting the pathogenesis of ALS/PDC.
References
[1]
Cox, P.A.; Sacks, O.W. Cycad neurotoxins, consumption of flying foxes, and ALS-PDC disease in Guam. Neurology？2002, 58, 956–959. 11914415
[2]
Kisby, G.E.; Ellison, M.; Spencer, P.S. Content of the neurotoxins cycasin (methylazoxymethanol beta-D-glucoside) and BMAA (beta-N-methylamino-L-alanine) in cycad flour prepared by Guam Chamorros. Neurology？1992, 42, 1336–1340, doi:10.1212/WNL.42.7.1336. 1620343
[3]
Cox, P.A.; Banack, S.A.; Murch, S.J. Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proc. Natl. Acad. Sci. USA？2003, 100, 13380–13383, doi:10.1073/pnas.2235808100. 14612559
[4]
Murch, S.J.; Cox, P.A.; Banack, S.A. A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc. Natl. Acad. Sci. USA？2004, 101, 12228–12231, doi:10.1073/pnas.0404926101. 15295100
[5]
Banack, S.A.; Johnson, H.E.; Cheng, R.; Cox, P.A. Production of the Neurotoxin BMAA by a Marine Cyanobacterium. Mar. Drugs？2007, 5, 180–196, doi:10.3390/md504180. 18463731
[6]
Metcalf, J.S.; Banack, S.A.; Lindsay, J.; Morrison, L.F.; Cox, P.A.; Codd, G.A. Co-occurrence of beta-N-methylamino-L-alanine, a neurotoxic amino acid with other cyanobacterial toxins in British waterbodies, 1990–2004. Environ. Microbiol.？2008, 10, 702–708, doi:10.1111/j.1462-2920.2007.01492.x. 18237305
[7]
Jonasson, S.; Eriksson, J.; Berntzon, L.; Spacil, Z.; Ilag, L.L.; Ronnevi, L.O.; Rasmussen, U.; Bergman, B. Transfer of a cyanobacterial neurotoxin within a temperate aquatic ecosystem suggests pathways for human exposure. Proc. Natl. Acad. Sci. USA？2010, 107, 9252–9257, doi:10.1073/pnas.0914417107. 20439734
[8]
Johnson, H.E.; King, S.R.; Banack, S.A.; Webster, C.; Callanaupa, W.J.; Cox, P.A. Cyanobacteria (Nostoc commune) used as a dietary item in the Peruvian highlands produce the neurotoxic amino acid BMAA. J. Ethnopharmacol.？2008, 118, 159–165, doi:10.1016/j.jep.2008.04.008. 18495396
Murch, S.J.; Cox, P.A.; Banack, S.A.; Steele, J.C.; Sacks, O.W. Occurrence of beta-methylamino-l-alanine (BMAA) in ALS/PDC patients from Guam. Acta Neurol. Scand.？2004, 110, 267–269, doi:10.1111/j.1600-0404.2004.00320.x. 15355492
[11]
Pablo, J.; Banack, S.A.; Cox, P.A.; Johnson, T.E.; Papapetropoulos, S.; Bradley, W.G.; Buck, A.; Mash, D.C. Cyanobacterial neurotoxin BMAA in ALS and Alzheimer's disease. Acta Neurol. Scand.？2009.
[12]
Papapetropoulos, S. Is there a role for naturally occurring cyanobacterial toxins in neurodegeneration? The beta-N-methylamino-L-alanine (BMAA) paradigm. Neurochem. Int.？2007, 50, 998–1003, doi:10.1016/j.neuint.2006.12.011. 17296249
[13]
Snyder, L.R.; Cruz-Aguado, R.; Sadilek, M.; Galasko, D.; Shaw, C.A.; Montine, T.J. Lack of cerebral bmaa in human cerebral cortex. Neurology？2009, 72, 1360–1361, doi:10.1212/WNL.0b013e3181a0fed1. 19365059
Weiss, J.H.; Christine, C.W.; Choi, D.W. Bicarbonate dependence of glutamate receptor activation by beta-N-methylamino-L-alanine: Channel recording and study with related compounds. Neuron？1989, 3, 321–326, doi:10.1016/0896-6273(89)90256-0. 2561969
[17]
Brownson, D.M.; Mabry, T.J.; Leslie, S.W. The cycad neurotoxic amino acid, beta-N-methylamino-L-alanine (BMAA), elevates intracellular calcium levels in dissociated rat brain cells. J. Ethnopharmacol.？2002, 82, 159–167, doi:10.1016/S0378-8741(02)00170-8. 12241991
[18]
Cruz-Aguado, R.; Winkler, D.; Shaw, C.A. Lack of behavioral and neuropathological effects of dietary beta-methylamino-L-alanine (BMAA) in mice. Pharmacol. Biochem. Behav.？2006, 84, 294–299, doi:10.1016/j.pbb.2006.05.012. 16808967
[19]
Karamyan, V.T.; Speth, R.C. Animal models of BMAA neurotoxicity: A critical review. Life Sci.？2008, 82, 233–246, doi:10.1016/j.lfs.2007.11.020. 18191417
Ganetzky, B.; Flanagan, J.R. On the relationship between senescence and age-related changes in two wild-type strains of Drosophila melanogaster. Exp. Gerontol.？1978, 13, 189–196, doi:10.1016/0531-5565(78)90012-8. 99324
[22]
Le Bourg, E.; Lints, F.A. Hypergravity and aging in Drosophila melanogaster. 4. Climbing activity. Gerontology？1992, 38, 59–64, doi:10.1159/000213307. 1612462
[23]
Le Bourg, E.; Buecher, C. Learned suppression of photopositive tendencies in Drosophila melanogaster. Anim. Learn. Behav.？2002, 30, 330–341, doi:10.3758/BF03195958. 12593325
[24]
Seugnet, L.; Suzuki, Y.; Stidd, R.; Shaw, P.J. Aversive phototaxic suppression: Evaluation of a short-term memory assay in Drosophila melanogaster. Genes Brain Behav.？2009, 8, 377–389, doi:10.1111/j.1601-183X.2009.00483.x. 19220479
Ratnaparkhi, A.; Lawless, G.M.; Schweizer, F.E.; Golshani, P.; Jackson, G.R. A Drosophila model of ALS: Human ALS-associated mutation in VAP33A suggests a dominant negative mechanism. PLoS ONE？2008, 3, e2334, doi:10.1371/journal.pone.0002334. 18523548
[27]
Tsuda, H.; Han, S.M.; Yang, Y.; Tong, C.; Lin, Y.Q.; Mohan, K.; Haueter, C.; Zoghbi, A.; Harati, Y.; Kwan, J.; Miller, M.A.; Bellen, H.J. The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors. Cell？2008, 133, 963–977, doi:10.1016/j.cell.2008.04.039. 18555774
[28]
Watson, M.R.; Lagow, R.D.; Xu, K.; Zhang, B.; Bonini, N.M. A drosophila model for amyotrophic lateral sclerosis reveals motor neuron damage by human SOD1. J. Biol. Chem.？2008, 283, 24972–24981, doi:10.1074/jbc.M804817200. 18596033
[29]
Benzer, S. From the gene to behavior. Jama？1971, 218, 1015–1022, doi:10.1001/jama.1971.03190200047010. 4942064
[30]
Benzer, S. Genetic dissection of behavior. Sci. Am.？1973, 229, 24–37. 4202065
[31]
Hotta, Y.; Benzer, S. Mapping of behavior in Drosophila mosaics. Symp. Soc. Dev. Biol.？1973, 31, 129–167. 4205816
[32]
Hirsch, J.; Boudreau, J.C. Studies in experimental behavior genetics. I. The heritability of phototaxis in a population of Drosophila melanogaster. J. Comp. Physiol. Psychol.？1958, 51, 647–651, doi:10.1037/h0039498. 13620797
[33]
Hendel, T.; Michels, B.; Neuser, K.; Schipanski, A.; Kaun, K.; Sokolowski, M.B.; Marohn, F.; Michel, R.; Heisenberg, M.; Gerber, B. The carrot, not the stick: appetitive rather than aversive gustatory stimuli support associative olfactory learning in individually assayed Drosophila larvae. J. Comp. Physiol. A Neuroethol. Sens. Neural. Behav. Physiol.？2005, 191, 265–279, doi:10.1007/s00359-004-0574-8. 15657743
[34]
Le Bourg, E. Effects of aging on learned suppression of photopositive tendencies in Drosophila melanogaster. Neurobiol. Aging？2004, 25, 1241–1252, doi:10.1016/j.neurobiolaging.2003.12.004. 15312970
[35]
Meunier, N.; Marion-Poll, F.; Rospars, J.P.; Tanimura, T. Peripheral coding of bitter taste in Drosophila. J. Neurobiol.？2003, 56, 139–152, doi:10.1002/neu.10235. 12838579
[36]
Quinn, W.G.; Harris, W.A.; Benzer, S. Conditioned behavior in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA？1974, 71, 708–712, doi:10.1073/pnas.71.3.708. 4207071
[37]
Bradley, W.G.; Mash, D.C. Beyond Guam: The cyanobacteria/BMAA hypothesis of the cause of ALS and other neurodegenerative diseases. Amyotroph. Lateral. Scler.？2009, 10, 7–20. 19929726
[38]
Weiss, J.H.; Koh, J.Y.; Choi, D.W. Neurotoxicity of beta-N-methylamino-L-alanine (BMAA) and beta-N-oxalylamino-L-alanine (BOAA) on cultured cortical neurons. Brain Res.？1989, 497, 64–71, doi:10.1016/0006-8993(89)90970-0. 2551452
[39]
Ross, S.M.; Seelig, M.; Spencer, P.S. Specific antagonism of excitotoxic action of 'uncommon' amino acids assayed in organotypic mouse cortical cultures. Brain Res.？1987, 425, 120–127, doi:10.1016/0006-8993(87)90490-2. 3123008
Copani, A.; Canonico, P.L.; Catania, M.V.; Aronica, E.; Bruno, V.; Ratti, E.; van Amsterdam, F.T.; Gaviraghi, G.; Nicoletti, F. Interaction between beta-N-methylamino-L-alanine and excitatory amino acid receptors in brain slices and neuronal cultures. Brain Res.？1991, 558, 79–86, doi:10.1016/0006-8993(91)90716-9. 1657313
[43]
Rakonczay, Z.; Matsuoka, Y.; Giacobini, E. Effects of L-beta-N-methylamino-L-alanine (L-BMAA) on the cortical cholinergic and glutamatergic systems of the rat. J. Neurosci. Res.？1991, 29, 121–126, doi:10.1002/jnr.490290114. 1653366
[44]
Liu, X.; Rush, T.; Zapata, J.; Lobner, D. beta-N-methylamino-l-alanine induces oxidative stress and glutamate release through action on system Xc(-). Exp. Neurol.？2009, 217, 429–433, doi:10.1016/j.expneurol.2009.04.002. 19374900
[45]
Lobner, D. Mechanisms of beta-N-methylamino-L-alanine induced neurotoxicity. Amyotroph. Lateral. Scler.？2009, 10, 56–60, doi:10.3109/17482960903269062. 19929733
[46]
Nunn, P.B. Three phases of research on beta-N-methylamino-L-alanine (BMAA)—A neurotoxic amino acid. Amyotroph. Lateral. Scler.？2009, 10, 26–33, doi:10.3109/17482960903272975. 19929728
[47]
Nunn, P.B.; Ponnusamy, M. Beta-N-methylaminoalanine (BMAA): Metabolism and metabolic effects in model systems and in neural and other tissues of the rat in vitro. Toxicon？2009, 54, 85–94, doi:10.1016/j.toxicon.2009.03.008. 19285998
