Environmental Neurotoxins Linked to a Prototypical Neurodegenerative Disease

Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) is a prototypical neurodegenerative disease with a dominant or exclusive environmental etiology that is acquired early in life and expressed clinically decades later. Although the precise cause of this tauopathy is unknown, much evidence points to the traditional use of cycad seed (. Cycas spp.) for medicine and/or food, cultural practices that have declined coincident with the changing clinical face and gradual disappearance of high-incidence ALS-PDC foci on Guam, Japan (Honshu Island), and New Guinea (West Papua, Indonesia). Two neurotoxic agents in cycad seed occupy current research attention: (1) the genotoxin methylazoxymethanol (MAM, aglycone of the principal cycad toxin, cycasin), which can dramatically disrupt brain development in rodents, and (2) β-. N-methylamino-. l-alanine (. l-BMAA), a minor cycad component and globally widespread cyanobacterial product with neurotoxic properties. Solving the etiology and pathogenesis of ALS-PDC should support the identification of environmental risk factors for neuropathologically related diseases, including sporadic ALS and Alzheimer's disease.