Hypothesis: Etiologic and Molecular Mechanistic Leads for Sporadic Neurodegenerative Diseases Based on Experience With Western Pacific ALS/PDC

Abstract

Seventy years of research on Western Pacific amyotrophic lateral sclerosis and Parkinsonism-dementia Complex (ALS/PDC) have provided invaluable data on the etiology, molecular pathogenesis and latency of this disappearing, largely environmental neurodegenerative disease. ALS/PDC is linked to genotoxic chemicals (notably methylazoxymethanol, MAM) derived from seed of the cycad plant ( Cycas spp.) that were used as a traditional food and/or medicine in all three disease-affected Western Pacific populations. MAM, nitrosamines and hydrazines generate methyl free radicals that damage DNA (in the form of O 6 -methylguanine lesions) that can induce mutations in cycling cells and degenerative changes in post-mitotic cells, notably neurons. This paper explores exposures to naturally occurring and manmade sources of nitrosamines and hydrazines in association with sporadic forms of ALS (with or without frontotemporal degeneration), progressive supranuclear palsy, and Alzheimer disease. Research approaches are suggested to examine whether these associations might have etiological significance. Lay Summary Unknown environmental exposures are thought to be risk factors for non-inherited forms of certain progressive brain diseases, such as sporadic forms of amyotrophic lateral sclerosis (sALS), progressive supranuclear palsy (sPSP), and Alzheimer's disease (sAD). Related progressive and fatal brain disorders coalesce in a single neurodegenerative disease of largely environmental origin (ALS-Parkinsonism-dementia Complex) that has affected three genetically distinct populations residing in islands of the Western Pacific region. Prolonged study of this prototypical neurodegenerative disease has provided invaluable information on the probable environmental cause (specific chemical genotoxins) and molecular mechanisms (unrepaired nerve cell DNA-damage) by which brain degeneration begins, evolves and, years or decades later, clinical signs appear, and progress. This information is used as a foundation to explore whether chemically related genotoxins (nitrosamines, hydrazines) are possible risk factors for sALS, sPSP, and sAD. Methods to test this hypothesis in the field and laboratory are proposed.

Warning on False or True Morels and Button Mushrooms with Potential Toxicity Linked to Hydrazinic Toxins: An Update

“…It was commonly believed by mushroom pickers that this species was not toxic since contradictory poisoning experience was reported. As a result, it is found as edible in mushroom lists proposed in France and Finland [ 16 ] and reported as gourmet food or as rejuvenating [ 9 , 13 ]. As popular belief is hard to change, its deliberate consumption was also reported in the Scandinavian countries.…”

“…The toxic compounds responsible for this acute toxicity are not known. However, the presence in the various Agaricus spp of a natural toxicant called agaritine and containing an hydrazinic moiety in its structure is worth considering, since toxicity of hydrazine derivatives, due to their high reactivity as chemical radicals, has been known for years [ 13 , 45 , 46 ]. Furthermore, curiously, agaritine poisoning is less and less mentioned in the recent literature except in two isolated studies published in 2014 [ 5 , 33 ] and an up to date is necessary.…”

“…It was recently pointed out that, due to the gyromitrin toxin, false morels Gyromitra spp. could play a role in sporadic amyotrophic lateral sclerosis (ALS), a neurodegenerative disease [ 12 , 13 ]. Gyromitrin is a hazardous neurotoxic hydrazine derivative [ 14 ].…”

ATM Protein Kinase: Old and New Implications in Neuronal Pathways and Brain Circuitry

“…As A-T, there are Nijmegen breakage syndrome (NBS), Bloom syndrome (BS), and A-T-like disorder, all of which are characterized by chromosomal instability, neurodegeneration, oxidative stress, and immunodeficiency [ 11 ]. DNA damage, cell-cycling abnormalities, cerebellar pathology, tauopathy linked to the production of Reactive Oxygen Species (ROS), and alterations in epigenetic pathways have also been demonstrated in the Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-dementia Complex (ALS/PDC) syndrome [ 49 ]. Accordingly, in a recent study, TDP-43, which has been shown to participate in DNA repair pathways, has been found in the tau-dominated polyproteinopathy of Western Pacific ALS/PDC [ 50 ], in particular in the spinal cord, limbic, and cortical regions of patients.…”

Metal(loid)s role in the pathogenesis of amyotrophic lateral sclerosis: Environmental, epidemiological, and genetic data

“…The role of environmental factors has been frequently reported in systematic reviews and meta-analysis of observational studies (see for example Yu et al, 2014;Oskarsson et al, 2015;Bozzoni et al, 2016;Wang et al, 2017;Riancho et al, 2018). Toxins from cyanobacteria, infectious agents, and mushrooms (Cox et al, 2016;Castanedo-Vazquez et al, 2019;French et al, 2019;Spencer et al, 2019;Fiore et al, 2020), hydrazine from fungal or industrial origin (Spencer, 2019;Spencer et al, 2019), cigarette smoking (Calvo et al, 2016), alcohol consumption (de Jong et al, 2012), physical work (Huisman et al, 2013), agonistic sport activities (Chiò et al, 2005;Gotkine et al, 2014;Visser et al, 2019), military service (Binazzi et al, 2009;Drouet et al, 2010;Beard and Kamel, 2015), head trauma (Filippini et al, 2020a;McKee et al, 2010;Seelen et al, 2014), exposure to electromagnetic fields (Hakansson et al, 2003;Gunnarsson and Bodin, 2018), pesticides (Chiò et al, 2009;Malek et al, 2012;Kamel et al, 2012;Vinceti et al, 2012;Vinceti et al, 2017), and Pb (Filippini et al, 2020b;Oh et al, 2007) are the environmental culprits most commonly cited for ALS (Zufiria et al, 2016), sometimes in controversial ways.…”