Lathyrism, a motorneurone disease of India and Africa, is caused by beta-oxalylaminoalanine (L-BOAA) which is present in the seeds of the legume Lathyrus sativus. The seeds of this plant are ground to a flour and used as food. Circumstantial evidence suggests that a second neurotoxic non-protein amino acid, beta-methylaminoalanine (L-BMAA), which is present in seeds of Cycas circinalis, which is used as a source of starchy foods by the Chamorro people of Guam and elsewhere in the western Pacific, may be responsible for amyotrophic lateral sclerosis- Parkinsonism dementia (ALS-PDC) among these people. Both of these non- protein amino acids induce motor system disorders when fed to macaques and both are glutamate agonists. Another glutamate agonist domoic acid, which was implicated in Canada in a 1987 outbreak of neurologic disorders by persons who had eaten contaminated mussels, also has similar ionic functions in almost the same stereochemical orientation as do glutamic acid, NMDA, kainic acid, L-BOAA and, significantly, the physiological-stable complex of L-BMAA with carbonate, a common physiological ion. In order to provide more comprehensive data on the potential toxicity of Cycas circinalis from Guam it is proposed to determine the concentrations of not only free L-BMAA, but also peptide-bound L-BMAA, L-BMAA precursors and related glutamate analogues in all organs of the plant using material from different plant populations. The structures of any unusual amino acids or related compounds will be determined, and isolated compounds will be evaluated for neurotoxicity. We have already detected several unknown ninhydrin-positive compounds in the extract of Cycas circinalis seeds in addition to the known L-BMAA. It is possible that some forms of Parkinson's and Alzheimer's diseases and ALS found in the continental United States may involve dietary factors. It is therefore also proposed to determine simultaneously whether any of the major crop species that contribute to the American diet contain glutamate agonists or antagonists which, if ingested for a prolonged period, could induce motor systems disorders. Plant extracts will be analyzed with high voltage electrophoresis, an automatic amino acid analyzer and GC/MS. Isolations will be made on ion-exchange columns. Neurotoxicity will first be evaluated in cultured tissues. Compounds will be selected for animal testing on the basis of ionic functions, stereochemistry and glutamate agonist activity.
