BMAA--an unusual cyanobacterial neurotoxin.
Abstract The toxin ss-N-methylamino-L-alanine (BMAA) was proposed to contribute to the ALS/Parkinsonism-dementia complex of Guam (ALS/PDC) based on its presence in cycad seeds, which constituted a dietary item in afflicted populations, and its ability to induce a similar disease phenotype in primates. Although the role of BMAA in human neurodegenerative disease is still highly debated, it appears to injure cultured neurons via mechanisms involving overactivation of neuroexcitatory glutamate receptors. However, BMAA lacks the side-chain acidic group of glutamate and other excitatory amino acids, and in its place has an amino group. In past studies we found that toxic and excitatory effects of BMAA on cultured neurons were dependent upon the presence of bicarbonate in the medium, and suggested that formation of a carbamate adduct of the side-chain amino group might produce structures capable of activating glutamate receptors. Also, while BMAA is a weal agonist at NMDA-type glutamate receptors, we found low levels of BMAA to selectively damage vulnerable sub-populations of neurons, including motor neurons, via activation of AMPA/kainate receptors. Recent reports that BMAA is produced by cyanobacteria in diverse ecosystems and is present in brain and spinal cord tissues from sporadic ALS and Alzheimer's patients as well as brains of ALS/PDC patients provide strong motivation for further investigations of its toxic mechanisms and contributions to human disease.
Vyas
Kaivalya J
KJ
Departments of Neurology & Anatomy and Neurobiology, University of California-Irvine, Irvine, California 92697-4292, USA.
Weiss
John H
JH
D000599:Amino Acids, Diamino / Q000494:pharmacology / Q000633:toxicity*; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology / Q000633:toxicity*; D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D000458:Cyanobacteria / Q000737:chemistry*; D006801:Humans; D009046:Motor Neurons / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology*; D017470:Receptors, Glutamate / Q000145:classification / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000599:Amino Acids, Diamino; D000600:Amino Acids, Dicarboxylic; D001639:Bicarbonates; D009498:Neurotoxins; D017470:Receptors, Glutamate; C064612:alpha-N-carboxy-beta-N-methylaminoalanine