BMAA selectively injures motor neurons via AMPA/kainate receptor activation.
The toxin beta-methylamino-l-alanine (BMAA) has been proposed to contribute to amyotrophic lateral sclerosis-Parkinsonism Dementia Complex of Guam (ALS/PDC) based on its ability to induce a similar disease phenotype in primates and its presence in cycad seeds, which constituted a dietary item in afflicted populations. Concerns about the apparent low potency of this toxin in relation to estimated levels of human ingestion led to a slowing of BMAA research. However, recent reports identifying potential new routes of exposure compel a re-examination of the BMAA/cycad hypothesis. BMAA was found to induce selective motor neuron (MN) loss in dissociated mixed spinal cord cultures at concentrations ( approximately 30 muM) significantly lower than those previously found to induce widespread neuronal degeneration. The glutamate receptor antagonist NBQX prevented BMAA-induced death, implicating excitotoxic activation of AMPA/kainate receptors. Using microfluorimetric techniques, we further found that BMAA induced preferential [Ca(2+)](i) rises and selective reactive oxygen species (ROS) generation in MNs with minimal effect on other spinal neurons. Cycad seed extracts also triggered preferential AMPA/kainate-receptor-dependent MN injury, consistent with the idea that BMAA is a crucial toxic component in this plant. Present findings support the hypothesis that BMAA may contribute to the selective MN loss in ALS/PDC.
Rao
Shyam D
SD
Department of Anatomy and Neurobiology, 2101 Gillespie Building, University of California, Irvine, Irvine, CA 92697-4292, USA.
Banack
Sandra Anne
SA
Cox
Paul Alan
PA
Weiss
John H
JH
D000599:Amino Acids, Diamino / Q000008:administration & dosage / Q000633:toxicity*; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000087522:Cyanobacteria Toxins; D029784:Cycas / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity; D010936:Plant Extracts / Q000008:administration & dosage / Q000633:toxicity; D010939:Plant Poisoning / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011810:Quinoxalines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012639:Seeds / Q000737:chemistry; D013116:Spinal Cord / Q000166:cytology
D000599:Amino Acids, Diamino; D002118:Calcium; D000087522:Cyanobacteria Toxins; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D010936:Plant Extracts; D011810:Quinoxalines; D017382:Reactive Oxygen Species; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C001824:beta-N-methylamino-L-alanine; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline