Abstract
Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) is a disappearing prototypical neurodegenerative disorder (tau-dominated polyproteinopathy) linked with prior exposure to phytogenotoxins in cycad seed used for medicine and/or food. The principal cycad genotoxin, methylazoxymethanol (MAM), forms reactive carbon-centered ions that alkylate nucleic acids in fetal rodent brain and, depending on the timing of systemic administration, induces persistent developmental abnormalities of the cortex, hippocampus, cerebellum, and retina. Whereas administration of MAM prenatally or postnatally can produce animal models of epilepsy, schizophrenia or ataxia, administration to adult animals produces little effect on brain structure or function. The neurotoxic effects of MAM administered to rats during cortical brain development (specifically, gestation day 17) are used to model the histological, neurophysiological and behavioral deficits of human schizophrenia, a condition that may precede or follow clinical onset of motor neuron disease in subjects with sporadic ALS and ALS/PDC. While studies of migrants to and from communities impacted by ALS/PDC indicate the degenerative brain disorder may be acquired in juvenile and adult life, a proportion of indigenous cases shows neurodevelopmental aberrations in the cerebellum and retina consistent with MAM exposure in utero. MAM induces specific patterns of DNA damage and repair that associate with increased tau expression in primary rat neuronal cultures and with brain transcriptional changes that parallel those associated with human ALS and Alzheimer’s disease. We examine MAM in relation to neurodevelopment, epigenetic modification, DNA damage/replicative stress, genomic instability, somatic mutation, cell-cycle reentry and cellular senescence. Since the majority of neurodegenerative disease lacks a solely inherited genetic basis, research is needed to explore the hypothesis that early-life exposure to genotoxic agents may trigger or promote molecular events that culminate in neurodegeneration.
Highlights
Work on the etiology of Western Pacific amyotrophic lateral sclerosis (ALS)/PDC and related tauopathies raises some important questions
A common theme among amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC) and related neurodegenerative disorders is that cell-cycle changes and genomic instability occurring during brain development lead to the appearance and progression of brain disease in adulthood
Exposure to cycad genotoxins during early human brain development might be an important driver of the ensuing pathological features of ALS/PDC, comparable to Huntington’s disease (HD) where a mutant gene (Htt) perturbs neurodevelopment that results in age-related decline in cognitive function (Ruzo et al, 2018; van der Plas et al, 2019; Barnat et al, 2020; Hickman et al, 2021; Schultz et al, 2021)
Summary
A developmental origin for neurodegenerative disorders, including amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD), Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD), and mild cognitive impairment (MCI), has been considered for many years (Gardener et al, 2010; Kovacs et al, 2014; Arendt et al, 2017; Ruzo et al, 2018; Wiatr et al, 2018; Kiernan et al, 2019; Starr, 2019; Lulé et al, 2020; Wang Z. et al, 2020), and recent clinical, genomic and molecular studies have uncovered evidence linking neurodevelopmental changes and neurodegenerative diseases. Familial progressive neurodegenerative diseases have provided clues about the role of toxic species of misprocessed peptides and proteins caused by specific mutations, sporadic forms of neurodegenerative disorders without clear evidence of a genetic etiology comprise the majority of cases. This suggests that environmental factors with potential developmental genotoxicity should be considered in the etiology and pathogenesis of sporadic forms of neurodegenerative diseases. A common theme among ALS/PDC and related neurodegenerative disorders is that cell-cycle changes and genomic instability occurring during brain development lead to the appearance and progression of brain disease in adulthood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
