Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

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.

Early-onset, conjugal, twin-discordant, and clusters of sporadic ALS: Pathway to discovery of etiology via lifetime exposome research

“…While unproven, it seems plausible that persons with larger exposures to the culpable environmental agent(s) developed motorsystem disease at an early age (expressed clinically as ALS) while lesser-exposed subjects who survived fatal motor neuron loss developed mixed forms of ALS/PDC expressed clinically later in life. Additionally, on Guam in particular, many with and without ALS/PDC had a stationary pigmentary retinopathy ( Campbell et al, 1993 ), which was replicated in laboratory species treated with cycasin or MAM at an age equivalent to the second trimester of human pregnancy ( Spencer, 2020 ; Kisby and Spencer, 2021 ). While the exposure age for acquisition of neurodegenerative disease in later life is unknown, subjects who moved from the high-incidence focus in Kii-Japan developed motor neuron disease 1–7 decades later ( Yoshida et al, 1998 ; Tsunoda et al, 2017 ), while exposure to Guam during adolescence/young adulthood, but not childhood, correlated strongly with ALS/PDC ( Borenstein et al, 2007 ).…”

“…downregulated in mid to late S-phase of the cell cycle (Mostofa et al, 2018) such that post-mitotic cells have low MGMT levels (Kisby and Spencer, 2021). Noteworthy is that changes in gene and protein expression of MGMT have been found in Alzheimer disease (Oláh et al, 2015;Chung et al, 2022;Kisby et al, 2022).…”

Nodding syndrome: A key role for sources of nutrition?

“…Similarly, methylazoxymethanol (MAM), the free-radical-generating aglycone of cycasin, increases DNA adducts (O 6 -mG, N7-mG) and elevates tau mRNA expression in rat neuronal cultures treated with glutamate [ 60 ] and, in mice, modulates brain cellular pathways involved in neurodegenerative disease and cancer in a DNA damage-linked manner [ 61 , 62 ]. MAM-β-D-glucoside (cycasin) is the principal toxin in cycad seed, the traditional food use of which by the Chamorro people of Guam is etiologically associated with the Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex, a tau-dominated polyproteinopathy that can begin early in life [ 63 ] and has a neuropathologic profile with some overlap with that of Nodding syndrome [ 12 ]. While there is some evidence that dietary B vitamin (B12, B6) supplementation can slow the advance of Mild Cognitive Impairment and AD [ 64 , 65 ].…”

The Potential Connection between Molecular Changes and Biomarkers Related to ALS and the Development and Regeneration of CNS

“…The supporting evidence for this point of view has been found from recent investigations, where induced pluripotent stem cells (iPSCs) or induced neurons (iNs) that were derived from AD patients showed a de-differentiated phenotype, reminiscent of an immature (i.e., progenitor-like) neuronal state. These cells also show signs of a cell cycle re-entry [ 115 , 116 ]. These observations suggest that the process of de-differentiation in response to injury represents the link between neuronal degeneration, development, and regeneration and this might apply to ALS as well.…”