Beyond Guam: The cyanobacteria/BMAA hypothesis of the causeof ALS and other neurodegenerative diseases

摘要

Excitement about neurogenetics in the last two decades has diverted attention from environmental causes of sporadic ALS.Fifty years ago endemic foci of ALS with a frequency one hundred times that in the rest of the world attracted attentionsince they offered the possibility of finding the cause for non-endemic ALS throughout the world. Research on Guamsuggested that ALS, Parkinson's disease and dementia (the ALS/PDC complex) was due to a neurotoxic non-protein aminoacid, β-methylamino-L-alanine (BMAA), in the seeds of the cycad Cycas micronesica. Recent discoveries that found thatBMAA is produced by symbiotic cyanobacteria within specialized roots of the cycads; that the concentration of protein-bound BMAA is up to a hundred-fold greater than free BMAA in the seeds and flour; that various animals forage on theseeds (flying foxes, pigs, deer), leading to biomagnification up the food chain in Guam; and that protein-bound BMAAoccurs in the brains of Guamanians dying of ALS/PDC (average concentration 627 μg/g, 5 mM) but not in control brainshave rekindled interest in BMAA as a possible trigger for Guamanian ALS/PDC. Perhaps most intriguing is the finding thatBMAA is present in brain tissues of North American patients who had died of Alzheimer's disease (average concentration95 μg/g, 0.8 mM); this suggests a possible etiological role for BMAA in non-Guamanian neurodegenerative diseases. Cyanobacteria are ubiquitous throughout the world, so it is possible that all humans are exposed to low amounts ofcyanobacterial BMAA, that protein-bound BMAA in human brains is a reservoir for chronic neurotoxicity, and thatcyanobacterial BMAA is a major cause of progressive neurodegenerative diseases including ALS worldwide. Though Montine et al., using different HPLC method and assay techniques from those used by Cox and colleagues,were unable to reproduce the findings of Murch et al., Mash and colleagues using the original techniques of Murch et al.have recently confirmed the presence of protein-bound BMAA in the brains of North American patients dying with ALSand Alzheimer's disease (concentrations >100 μg/g) but not in the brains of non-neurological controls or Huntington'sdisease. We hypothesize that individuals who develop neurodegenerations may have a genetic susceptibility because of inabilityto prevent BMAA accumulation in brain proteins and that the particular pattern of neurodegeneration that developsdepends on the polygenic background of the individual.