Western Pacific ALS-PDC: Evidence implicating cycad genotoxins

• Published in: Journal of the neurological sciences 2020-12, Vol.419, p.117185, Article 117185
• Main Authors: Spencer, Peter S., Palmer, Valerie S., Kisby, Glen E.
• Format: Article
• Language: English
• Subjects: Amyotrophic Lateral Sclerosis - chemically induced; Amyotrophic Lateral Sclerosis - epidemiology; Animals; Cell cycle; Cycasin; DNA damage; Guam; Humans; Indonesia; Japan; L-BMAA; Methylazoxymethanol; Mutagens; Neurodegeneration; Neurodegenerative Diseases; Sitosterol
• ISSN: 0022-510X; 1878-5883
• DOI: 10.1016/j.jns.2020.117185

Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS-PDC) is a disappearing neurodegenerative disorder of apparent environmental origin formerly hyperendemic among Chamorros of Guam-USA, Japanese residents of the Kii Peninsula, Honshu Island, Japan and Auyu-Jakai linguistic groups of Papua-Indonesia on the island of New Guinea. The most plausible etiology is exposure to genotoxins in seed of neurotoxic cycad plants formerly used for food and/or medicine. Primary suspicion falls on methylazoxymethanol (MAM), the aglycone of cycasin and on the non-protein amino acid β-N-methylamino-L-alanine, both of which are metabolized to formaldehyde. Human and animal studies suggest: (a) exposures occurred early in life and sometimes during late fetal brain development, (b) clinical expression of neurodegenerative disease appeared years or decades later, and (c) pathological changes in various tissues indicate the disease was not confined to the CNS. Experimental evidence points to toxic molecular mechanisms involving DNA damage, epigenetic changes, transcriptional mutagenesis, neuronal cell-cycle reactivation and perturbation of the ubiquitin-proteasome system that led to polyproteinopathy and culminated in neuronal degeneration. Lessons learned from research on ALS-PDC include: (a) familial disease may reflect common toxic exposures across generations, (b) primary disease prevention follows cessation of exposure to culpable environmental triggers; and (c) disease latency provides a prolonged period during which to intervene therapeutically. Exposure to genotoxic chemicals (“slow toxins”) in the early stages of life should be considered in the search for the etiology of ALS-PDC-related neurodegenerative disorders, including sporadic forms of ALS, progressive supranuclear palsy and Alzheimer's disease. •ALS-PDC has an epidemiological profile, long latency and multiple clinical features consistent with an acquired, environmental disease.•Most data favor food and/or medicinal exposure to cycad chemicals early in life, with years or decades passing before clinical disease appears.•The major cycad genotoxin methylazoxymethanol induces cerebellar, retinal, and systemic changes in animals that are associated with ALS-PDC.•The minor cycad toxin β-N-methylamino-L-alanine (L-BMAA) reproduces neuropathological features of ALS-PDC in rodents and primates.•Cessation of traditional cycad use correlates with the decline/disappearance of ALS-PDC in Guam-USA, Kii Penins