Abstract
Western Pacific ALS-PDC: a prototypical neurodegenerative disorder linked to DNA damage and aberrant proteogenesis?
Highlights
The Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC) has been described as a Rosetta Stone that bears the essential clue to understanding the etiopathogenesis of related neurodegenerative diseases
ALS-PDC is primarily if not exclusively an environmental disease: no gene mutations identified in related neurodegenerative disorders are found in Guam and Kii-Japan cases, and disease rates have steadily declined in the three affected populations
Among the many bioactive chemicals in cycad seed, two with neurotoxic properties are singled out as potential triggers of ALS-PDC: (a) methylazoxymethanol (MAM), a potent genotoxin, carcinogen and developmental neurotoxin that is stored in the plant as an inactive β-glucoside, the concentration of which in cycad flour correlates significantly with incidence rates for ALS and PD in males and females on Guam, unlike the concentration of (b) L-BMAA, a weak excitotoxic amino acid that is taken up by brain tissue and possibly undergoes proteogenesis, resulting in misfolded proteins; daily oral dosing of macaques with L-BMAA for up to 3 months induces a L-dopa-responsive, non-progressive motorsystem disorder with non-excitotoxic cortical and spinal motor neuron pathology
Summary
The Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC) has been described as a Rosetta Stone that bears the essential clue to understanding the etiopathogenesis of related neurodegenerative diseases. ALS-PDC is primarily if not exclusively an environmental disease: no gene mutations identified in related neurodegenerative disorders are found in Guam and Kii-Japan cases, and disease rates have steadily declined in the three affected populations.
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