Is Neurodegenerative Disease a Long-Latency Response to Early-Life Genotoxin Exposure?

Abstract

Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex, a disappearing neurodegenerative disease linked to use of the neurotoxic cycad plant for food and/or medicine, is intensively studied because the neuropathology (tauopathy) is similar to that of Alzheimer’s disease. Cycads contain neurotoxic and genotoxic principles, notably cycasin and methylazoxymethanol, the latter sharing chemical relations with nitrosamines, which are derived from nitrates and nitrites in preserved meats and fertilizers, and also used in the rubber and leather industries. This review includes new data that influence understanding of the neurobiological actions of cycad and related genotoxins and the putative mechanisms by which they might trigger neurodegenerative disease.

Assessment of the mutagenic and genotoxic activity of cyanobacterial toxin beta-N-methyl-amino-L-alanine in Salmonella typhimurium

“…It is known that methylamine in a reaction that is catalysed by semicarbazidesensitive amine oxidase is metabolised to yield formaldehyde, hydrogen peroxide and ammonium (Yu, 1990). Later on it has been shown that in rodents L-BMAA is taken up by brain tissue and is enzymatically metabolized to compounds with genotoxic properties including the carcinogen formaldehyde (Kisby et al, 1992;Kisby and Spencer, 2011). Moreover hydrogen peroxide formed in the reaction may be degraded by catalase and thereby reactive oxygen species are formed.…”

Cassava food toxins, konzo disease, and neurodegeneration in sub-Sahara Africans

“…These diseases include the amyotrophic lateral sclerosis/parkinsonism dementia complex among the Guamanians; neurolathyrism among Europeans, Indians, and populations of the Horn of Africa; and tropical ataxic neuropathy or konzo among sub-Sahara Africans. 1,2 We focus on the molecular determinants of susceptibility to konzo, a poorly known self-limited and irreversible upper motor neuron disease (spastic paraparesis) highly prevalent in Congo-Kinshasa, Mozambique, Tanzania, Central African Republic, Angola, and Cameroon. The main clinical picture consists of a symmetrical, permanent, and irreversible spastic paraparesis with no signs of sensory or genitourinary impairments.…”

The neurotoxin BMAA in aquatic systems : analysis, occurrence and effects

“…In subsequent studies, BMAA was shown to be neurotoxic (e.g. [31,44]), and BMAA exposure is at present regarded as one of the possible causes of ALS/PDC on Guam [45].…”

“…However, the role of BMAA in the aetiology of ALS/PDC on Guam was heavily debated (e.g. [72,139,140]) and BMAA exposure is at present regarded as one of the possible causes of Western Pacific ALS-PDC [45].…”

“…The current state of knowledge recognizes the neurotoxicity of BMAA on cellular and in vivo level [59,60] but an animal model for BMAA induced ALS is still lacking [60,66]. Recently, additional toxicity mechanisms have been proposed that might better explain the relation between BMAA exposure and the chronic nature of ALS/PDC [45,141]. Reports of BMAA in the brain of deceased patients suffering from ALS, PDC or Alzheimer's disease support the BMAA ALS/PDC hypothesis [69][70][71], however, these results could not be replicated by another research group [72][73][74].…”