Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

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 genotox...

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Autores principales:	Glen E. Kisby, Peter S. Spencer
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	neurodevelopment genomic instability cell-cycle re-entry schizophrenia amyotrophic lateral sclerosis atypical parkinsonism Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/a1499de9c02a498a8af69431a4716c47
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spelling	oai:doaj.org-article:a1499de9c02a498a8af69431a4716c472021-12-02T11:50:22ZGenotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease1662-453X10.3389/fnins.2021.752153https://doaj.org/article/a1499de9c02a498a8af69431a4716c472021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnins.2021.752153/fullhttps://doaj.org/toc/1662-453XWestern 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.Glen E. KisbyPeter S. SpencerFrontiers Media S.A.articleneurodevelopmentgenomic instabilitycell-cycle re-entryschizophreniaamyotrophic lateral sclerosisatypical parkinsonismNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Neuroscience, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	neurodevelopment genomic instability cell-cycle re-entry schizophrenia amyotrophic lateral sclerosis atypical parkinsonism Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	neurodevelopment genomic instability cell-cycle re-entry schizophrenia amyotrophic lateral sclerosis atypical parkinsonism Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Glen E. Kisby Peter S. Spencer Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease
description	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.
format	article
author	Glen E. Kisby Peter S. Spencer
author_facet	Glen E. Kisby Peter S. Spencer
author_sort	Glen E. Kisby
title	Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease
title_short	Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease
title_full	Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease
title_fullStr	Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease
title_full_unstemmed	Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease
title_sort	genotoxic damage during brain development presages prototypical neurodegenerative disease
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/a1499de9c02a498a8af69431a4716c47
work_keys_str_mv	AT glenekisby genotoxicdamageduringbraindevelopmentpresagesprototypicalneurodegenerativedisease AT petersspencer genotoxicdamageduringbraindevelopmentpresagesprototypicalneurodegenerativedisease
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Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

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