Food toxins, AMPA receptors, and motor neuron diseases

Environmental chemicals involved in the etiology of human neurodegenerative disorders are challenging to identify. Described here is research designed to determine the etiology and molecular pathogenesis of nerve cell degeneration in two little known corticomotoneuronal diseases with established environmental triggers. Both conditions are toxic-nutritional disorders dominated by persistent spastic weakness of the legs and degeneration of corresponding corticospinal pathways. Lathyrism, a disease caused by dietary dependence on grass pea (Lathyrus sativus), is mediated by a stereospecific plant amino acid (β-N-oxalylamino-L-alanine) that serves as a potent agonist at the (RS)-α-amino-3-hydroxy-5-methyl-isoxazole-4- propionic acid (AMPA) subclass of neuronal glutamate receptors. A neurologically similar disorder, konzo ('tied legs'), is found among protein- poor African communities that rely for food on cyanogen-containing cassava roots. Thiocyanate, the principal metabolite of cyanide, is an attractive etiologic candidate for konzo because it selectively promotes the action of glutamate at AMPA receptors. Studies are urgently needed to assess the health effects of cassava and other cyanogenic plants, components of which are widely used as food.