Introducing the Role of Genotoxicity in Neurodegenerative Diseases and Neuropsychiatric Disorders.

Decades of research have identified genetic and environmental factors involved in age-related neurodegenerative diseases and, to a lesser extent, neuropsychiatric disorders. Genomic instability, i.e., the loss of genome integrity, is a common feature among both neurodegenerative (mayo-trophic lateral sclerosis, Parkinson's disease, Alzheimer's disease) and psychiatric (schizophrenia, autism, bipolar depression) disorders. Genomic instability is associated with the accumulation of persistent DNA damage and the activation of DNA damage response (DDR) pathways, as well as pathologic neuronal cell loss or senescence. Typically, DDR signaling ensures that genomic and proteomic homeostasis are maintained in both dividing cells, including neural progenitors, and post-mitotic neurons. However, dysregulation of these protective responses, in part due to aging or environmental insults, contributes to the progressive development of neurodegenerative and/or psychiatric disorders. In this Special Issue, we introduce and highlight the overlap between neurodegenerative diseases and neuropsychiatric disorders, as well as the emerging clinical, genomic, and molecular evidence for the contributions of DNA damage and aberrant DNA repair. Our goal is to illuminate the importance of this subject to uncover possible treatment and prevention strategies for relevant devastating brain diseases.

MGMT, a risk factor for both genetic and environmental forms of dementia.

MGMT, the gene coding for the DNA-repair protein O6 -methylguanine methyltransferase, which has been recently shown to be a risk factor for inherited forms of Alzheimer's disease (AD), notably among women, might also be linked to Western Pacific amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC), one phenotype of which is an AD-like dementia. Guam ALS/PDC is strongly considered to be an environmental disorder caused by oral exposure to natural toxins (i.e., genotoxic/epigenotoxic chemicals), notably methylazoxymethanol (MAM) that alkylates guanine to form O6 -methylguanine, found in the seed of cycad plants traditionally used for food. Thus, the DNA-repair protein MGMT might participate in both AD and in the AD-related disorder ALS/PDC.

Role of Hydrazine-Related Chemicals in Cancer and Neurodegenerative Disease.

Hydrazine-related chemicals (HRCs) with carcinogenic and neurotoxic potential are found in certain mushrooms and plants used for food and in products employed in various industries, including aerospace. Their propensity to induce DNA damage (mostly O6-, N7- and 8-oxo-guanine lesions) resulting in multiple downstream effects is linked with both cancer and neurological disease. For cycling cells, unrepaired DNA damage leads to mutation and uncontrolled mitosis. By contrast, postmitotic neurons attempt to re-enter the cell cycle but undergo apoptosis or nonapoptotic cell death. Biomarkers of exposure to HRCs can be used to explore whether these substances are risk factors for sporadic amyotrophic laterals sclerosis and other noninherited neurodegenerative diseases, which is the focus of this paper.

Neuroprotein Targets of γ-Diketone Metabolites of Aliphatic and Aromatic Solvents That Induce Central-Peripheral Axonopathy.

Peripheral neuropathy associated with chronic occupational and deliberate overexposure to neurotoxic organic solvents results from axonal degeneration in the central and peripheral nervous system. Human and experimental studies show that axonopathy is triggered by the action of neuroprotein-reactive γ-diketone metabolites formed from exposure to certain aliphatic solvents (n-hexane, 2-hexanone) and aromatic compounds (1,2-diethylbenzene, 1,2-4-triethylbenzene, 6-acetyl-1,1,4,4-tetramethyl-7-ethyl-1,2,3,4-tetralin). Neuroprotein susceptibility is related primarily to their differential content of lysine, the ∊-amino group of which is targeted by γ-diketones. Specific neuroprotein targets have been identified, and the sequence of molecular mechanisms leading to axonal pathology has been illuminated. While occupational n-hexane neuropathy continues to be reported, lessons learned from its experimental study may have relevance to other causes of peripheral neuropathy, including those associated with aging and diabetes mellitus.

Decision-making under uncertainty in environmental health policy: new approaches.

Decision-making in environmental health policy is a complex procedure even in well-known conditions. Thus, in the case of uncertainty, decision-making becomes a hurdle race. We address scientific uncertainty, methods to reduce uncertainty, biomedical doubt and science communication, and the role of stakeholders, activists, lobbies and media that together influence policy decisions. We also consider the major responsibility and role of the medico-scientific community in this process. This community can and should teach the principle of scientific uncertainty to all stakeholders, advise policy-makers and underline the ethical issues, considering that our brains are not only the deposit of our humanity but also the route to environmental health and societal harmony.

Proteomic alterations of brain subcellular organelles caused by low-dose copper exposure: implication for Alzheimer's disease.

Excessive copper intake can lead to neurotoxicity, but there is a lack of comprehensive understanding on the potential impact of copper exposure especially at a low-dose on brain. We used 3xTg-AD mice to explore the potential neurotoxicity of chronic, low-dose copper treatment (0.13 ppm copper chloride in drinking water) on behavior and the brain hippocampal mitochondrial and nuclear proteome. Low-dose copper increased the spatial memory impairment of these animals, increased accumulation of intracellular amyloid 1-42 (Aß1-42), decreased ATP content, increased the positive staining of 8-hydroxyguanosine (8-OHdG), a marker of DNA oxidative damage, and caused apoptosis and a decrease in synaptic proteins. Mitochondrial proteomic analysis by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) revealed modulation of 24 hippocampal mitochondrial proteins (14 increased and 10 decreased) in copper-treated vs. untreated 3xTg-AD mice. Nuclear proteomic analysis revealed 43 modulated hippocampal nuclear proteins (25 increased and 18 decreased) in copper-treated 3xTg-AD vs. untreated mice. Classification of modulated mitochondrial and nuclear proteins included functional categories such as energy metabolism, synaptic-related proteins, DNA damage and apoptosis-related proteins, and oxidative stress-related proteins. Among these differentially expressed mitochondrial and nuclear proteins, nine proteins were abnormally expressed in both hippocampus mitochondria and nuclei, including electron transport chain-related proteins NADH dehydrogenase 1 alpha subcomplex subunit 10 (NDUAA), cytochrome b-c1 complex subunit Rieske (UCRI), cytochrome c oxidase subunit 5B (COX5B), and ATP synthase subunit d (ATP5H), glycolytic-related pyruvate kinase PKM (KPYM) and pyruvate dehydrogenase E1 component subunit alpha (ODPA). Furthermore, we found coenzyme Q10 (CoQ10), an endogenous mitochondrial protective factor/antioxidant, modulated the expression of 12 differentially expressed hippocampal proteins (4 increased and 8 decreased), which could be classified in functional categories such as glycolysis and synaptic-related proteins, oxidative stress-related proteins, implying that CoQ10 improved synaptic function, suppress oxidative stress, and regulate glycolysis. For the proteomics study, we validated the expression of several proteins related to synapses, DNA and apoptosis. The data confirmed that synapsin-2, a synaptic-related protein, was significantly decreased in both mitochondria and nuclei of copper-exposed 3xTg-AD mice. In mitochondria, dynamin-1 (DYN1), an apoptosis-related proteins, was significantly decreased. In the cellular nuclei, paraspeckle protein 1 (PSPC1) and purin-rich element-binding protein alpha (Purα), two DNA damage-related proteins, were significantly decreased and increased, respectively. We conclude that low-dose copper exposure exacerbates the spatial memory impairment of 3xTg-AD mice and perturbs multiple biological/pathogenic processes by dysregulating the mitochondrial and nuclear proteome. Exposure to copper might therefore contribute to the evolution of AD.

Nodding syndrome: A role for environmental biotoxins that dysregulate MECP2 expression?

Nodding syndrome is an epileptic encephalopathy associated with neuroinflammation and tauopathy. This initially pediatric brain disease, which has some clinical overlap with Methyl-CpG-binding protein 2 (MECP2) Duplication Syndrome, has impacted certain impoverished East African communities coincident with local civil conflict and internal displacement, conditions that forced dependence on contaminated food and water. A potential role in Nodding syndrome for certain biotoxins (freshwater cyanotoxins plus/minus mycotoxins) with neuroinflammatory, excitotoxic, tauopathic, and MECP2-dysregulating properties, is considered here for the first time.

Cramp-Fasciculation Syndrome Associated with Natural and Added Chemicals in Popular Food Items.

Cramp-fasciculation syndrome (CFS) is a rare and benign neuromuscular disorder that may initially masquerade as motor neuron disease/amyotrophic lateral sclerosis. While CFS may have a familial disposition, we report on cases associated with high consumption of popular food items. One set of patients reversibly experienced acute onset of headache, flushing, muscle stiffness and fasciculations following the consumption of umami-flavored food containing a large concentration of monosodium glutamate. A second group of patients consuming food derived from lupin seed developed acute cholinergic toxicity, CFS, and, with chronic intake, significant, self-limiting, but incompletely reversible upper and lower motor neuron deficits. While these cases may improve our knowledge about the possible causes of CFS, our series also demonstrates that excessive consumption of some popular foods is not harmless. This warrants further research on their safety at all stages of human development from a neurological point of view.

Neurological patients confronting climate change: A potential role for the glymphatic system and sleep.

Interest in the health consequences of climate change (global warming, heatwaves) has increased in the neurological community. This review addresses the impact of elevated ambient temperatures and heatwaves on patients with neurological and mental health disorders, including multiple sclerosis, synucleinopathies, dementia, epilepsies, mental health, and stroke. Patients with such conditions are highly vulnerable during heatwaves because of functional disorders affecting sleep, thermoregulation, autonomic system reactivity, mood, and cognitive ability. Several medications may also increase the risk of heatstroke. Special attention is devoted to the involvement of common underlying mechanisms, such as sleep and the glymphatic system. Disease prevention and patient care during heatwaves are major issues for caregivers. Beyond the usual recommendations for individuals, we favor artificially induced acclimation to heat, which provides preventive benefits with proven efficacy for healthy adults.

Corrected speciation and gyromitrin content of false morels linked to ALS patients with mostly slow-acetylator phenotypes.

A case-control study of sporadic amyotrophic lateral sclerosis (ALS) in a mountainous village in the French Alps discovered an association of cases with a history of eating wild fungi (false morels) collected locally and initially identified and erroneously reported as Gyromitra gigas. Specialist re-examination of dried specimens of the ALS-associated fungi demonstrated they were members of the G. esculenta group, namely G. venenata and G. esculenta, species that have been reported to contain substantially higher concentrations of gyromitrin than present in G. gigas. Gyromitrin is metabolized to monomethylhydrazine, which is responsible not only for the acute oral toxic and neurotoxic properties of false morels but also has genotoxic potential with proposed mechanistic relevance to the etiology of neurodegenerative disease. Most ALS patients had a slow- or intermediate-acetylator phenotype predicted by N-acetyltransferase-2 (NAT2) genotyping, which would increase the risk for neurotoxic and genotoxic effects of gyromitrin metabolites.

Animal models of brain maldevelopment induced by cycad plant genotoxins.

Cycads are long-lived tropical and subtropical plants that contain azoxyglycosides (e.g., cycasin, macrozamin) and neurotoxic amino acids (notably ß-N-methylamino-l-alanine l-BMAA), toxins that have been implicated in the etiology of a disappearing neurodegenerative disease, amyotrophic lateral sclerosis and parkinsonism-dementia complex that has been present in high incidence among three genetically distinct populations in the western Pacific. The neuropathology of amyotrophic lateral sclerosis/parkinsonism-dementia complex includes features suggestive of brain maldevelopment, an experimentally proven property of cycasin attributable to the genotoxic action of its aglycone methylazoxymethanol (MAM). This property of MAM has been exploited by neurobiologists as a tool to study perturbations of brain development. Depending on the neurodevelopmental stage, MAM can induce features in laboratory animals that model certain characteristics of epilepsy, schizophrenia, or ataxia. Studies in DNA repair-deficient mice show that MAM perturbs brain development through a DNA damage-mediated mechanism. The brain DNA lesions produced by systemic MAM appear to modulate the expression of genes that regulate neurodevelopment and contribute to neurodegeneration. Epigenetic changes (histone lysine methylation) have also been detected in the underdeveloped brain after MAM administration. The DNA damage and epigenetic changes produced by MAM and, perhaps by chemically related substances (e.g., nitrosamines, nitrosoureas, hydrazines), might be an important mechanism by which early-life exposure to genotoxicants can induce long-term brain dysfunction.

New clues to the elusive aetiology of nodding syndrome.

Nodding syndrome is a paediatric epileptic encephalopathy of unknown aetiology that affects children in impoverished communities of Eastern Africa subject to internal displacement. Set in southcentral South Sudan, where nodding syndrome first surfaced circa 1990, an important new study of recent-onset cases of nodding syndrome examined parasitic, bacterial, viral, immune-mediated, metabolic and nutritional factors associated with the brain disease. Infection with the nematode Mansonella perstans, but not with Onchocerca volvulus, was the most prominent finding in nodding syndrome cases versus controls. While M. perstans is unlikely to be causal of nodding syndrome, investigation of the freshwater habitats, where insect-to-human transmission of the filarial larvae takes place, may reveal a clue as to the aetiology of this neurodegenerative disease. The culpable environmental agent(s) must be able to induce neuroinflammation and tau pathology preferentially in infants and children.

Lathyrism in Spain: Lessons from 68 publications following the 1936-39 Civil War.

After the end of the Spanish Civil War (1936-1939), an estimated 1,000 patients presented with lathyrism due to their excessive and prolonged consumption of grasspea (Lathyrus sativus L.) against the backdrop of poverty, drought, and famine. Based on 68 scientific communications between 1941 and 1962 by qualified medical professionals, the disease emerged in different geographical locations involving selective populations: (1) farmers from extensive areas of central Spain, traditionally producers and consumers of grasspea; (2) immigrants in the industrial belt of Catalonia and in the Basque Country, areas with little or no production of grasspea, which was imported from producing areas; (3) workers in Galicia, an area where the legume is neither produced nor consumed, who were seasonally displaced to high-production areas of grasspea in Castille; and (4) inmates of overcrowded postwar Spanish prisons. Original reports included failed attempts by Carlos Jiménez Díaz (1898-1967) to induce experimental lathyrism, the neuropathology of lathyrism in early stages of the disease in two patients, as reported by Carlos Oliveras de la Riva (1914-2007), and the special susceptibility of children to develop a severe form of lathyrism after relatively brief periods of consumption of the neurotoxic seed of L. sativus. In the Spanish Basque Country, L. cicera L. (aizkol) was cultivated exclusively as animal fodder. Patients who were forced to feed on this plant developed unusual manifestations of lathyrism, such as axial myoclonus and severe neuropsychiatric disorders, unknown in other regions of the country and previously unreported. The postwar epidemic of lathyrism in Spain represents the most extensively studied outbreak of this self-limiting but crippling upper motor neuron disease.

Heatwaves and human sleep: Stress response versus adaptation.

The World Meteorological Organization considers a heatwave as "a period of statistically unusual hot weather persisting for a number of days and nights". Accompanying the ongoing global climate change, sharp heatwave bouts occur worldwide, growing in frequency and intensity, and beginning earlier in the season. Heatwaves exacerbate the risk of heat-related illnesses, hence human morbidity and mortality, particularly in vulnerable elderly and children. Heat-related illnesses present a continuum from normothermic (prickly heat, heat edema, heat cramps, heat tetany) to hyperthermic syndromes (from heat syncope and heat exhaustion to lethal heat stroke). Heat stroke may occur through passive heating and/or exertional exercise. "Normal sleep", such as observed in temperate conditions, is altered during heatwaves. Brisk excessive heat bouts shorten and fragment human sleep. Particularly, deep N3 sleep (formerly slow-wave sleep) and REM sleep are depleted, such as in other stressful situations. The resultant sleep loss is deleterious to cognitive performance, emotional brain function, behavior, and susceptibility to chronic health conditions and infectious diseases. Our group has previously demonstrated that sleep constitutes an adaptive mechanism during climatic heat acclimatization. In parallel, artificial heat acclimation procedures have been proposed in sports and military activities, and for the elderly. Other preventive actions should be considered, such as education and urban heat island cooling (vegetation, white paint), thus avoiding energy-hungry air conditioning.

Environmental neurology: Concepts and short history of an interdisciplinary approach to etiology, treatment and prevention.

Environmental Neurology (EN), a sub-discipline of Neurology and Neurological Sciences, favors an interdisciplinary collaboration allowing a holistic approach to understanding the impact of environmental factors on the nervous system and their relationship with neurological diseases. Several examples of diseases and conditions show the large scope of subjects addressed by EN. The EN sub-discipline focuses on both individual and population issues thus joining patient care and public health, respectively. Neuropathogenesis is addressed by several major questions: How do the environment and nervous system interact? Which exogenous factors can trigger neurological disease? When, where and how do they act? What are the therapeutic implications, and how can these disorders be controlled or prevented. To answer such questions, we address the incentive for, philosophy of and methods developed by EN, which seeks to safeguard Brain Health and, thus, the quality of life.

Association of N-nitrosodimethylamine exposure with cognitive impairment based on the clues of mice and humans.

N-nitrosodimethylamine (NDMA) is an environmental and food contaminant, but limited data to concern whether NDMA has adverse effects on the brain. This study first determined the concentration of NDMA in foods from aquaculture markets in Shenzhen, then analyzed the effects on C57BL/6 mice and further evaluated on the urine samples of elderly Chinese residents with normal cognition (NC, n = 144), cognitive decline (CD, n = 116) and mild cognitive impairment (MCI, n = 123). The excessive rate of NDMA in foods was 3.32% (27/813), with a exceeding range of 4.78-131.00 µg/kg. Behavioral tests showed that 60 days treatment of mice with 3 mg/kg NDMA reduced cognitive performance. Cognitive impairment in human was significantly associated with sex, educational levels, length of residence in Shenzhen, household registration, passive smoking, rice, fresh vegetables, bacon products. NDMA was detected in 55.4% (212/383) of urine samples, with a median concentration of 0.23 µg/L (1.20 × 10 -7-157.39 µg/L). The median concentration for NC, CD and MCI were 0.32, 0.27, and 0 µg/L, respectively. The urinary NDMA concentration had a strong negative correlation with cognitive impairment (Kendall's Tau-b = -0.89, P = 0.024). The median estimated daily intake (EDI) of NDMA was determined to be 6.63 ng/kg-bw/day. Taken together, there appears to be an association between NDMA and human and murine cognition, which provides a new clue to Alzheimer's disease (AD).

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

The identity and role of environmental factors in the etiology of sporadic amyotrophic lateral sclerosis (sALS) is poorly understood outside of three former high-incidence foci of Western Pacific ALS and a hotspot of sALS in the French Alps. In both instances, there is a strong association with exposure to DNA-damaging (genotoxic) chemicals years or decades prior to clinical onset of motor neuron disease. In light of this recent understanding, we discuss published geographic clusters of ALS, conjugal cases, single-affected twins, and young-onset cases in relation to their demographic, geographic and environmental associations but also whether, in theory, there was the possibility of exposure to genotoxic chemicals of natural or synthetic origin. Special opportunities to test for such exposures in sALS exist in southeast France, northwest Italy, Finland, the U.S. East North Central States, and in the U.S. Air Force and Space Force. Given the degree and timing of exposure to an environmental trigger of ALS may be related to the age at which the disease is expressed, research should focus on the lifetime exposome (from conception to clinical onset) of young sALS cases. Multidisciplinary research of this type may lead to the identification of ALS causation, mechanism, and primary prevention, as well as to early detection of impending ALS and pre-clinical treatment to slow development of this fatal neurological disease.

Parkinsonism and motor neuron disorders: Lessons from Western Pacific ALS/PDC.

Recognized worldwide as an unusual "overlap" syndrome, Parkinsonism and motor neuron disease, with or without dementia, is best exemplified by the former high-incidence clusters of Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) in Guam, USA, in the Kii Peninsula of Honshu Island, Japan, and in Papua, Indonesia, on the western side of New Guinea. Western Pacific ALS/PDC is a disappearing neurodegenerative disorder with multiple and sometime overlapping phenotypes (ALS, atypical parkinsonism, dementia) that appear to constitute a single disease of environmental origin, in particular from exposure to genotoxins/neurotoxins in seed of cycad plants (Cycas spp.) formerly used as a traditional source of food (Guam) and/or medicine (Guam, Kii-Japan, Papua-Indonesia). Seed compounds include the principal cycad toxin cycasin, its active metabolite methylazoxymethanol (MAM) and a non-protein amino acid ß-N-methylamino-L-alanine (L-BMAA); each reproduces components of ALS/PDC neuropathology when individually administered to laboratory species in single doses perinatally (MAM, L-BMAA) or repeatedly for prolonged periods to young adult animals (L-BMAA). Human exposure to MAM, a potent DNA-alkylating mutagen, also has potential relevance to the high incidence of diverse mutations found among Guamanians with/without ALS/PDC. In sum, seven decades of intensive study of ALS/PDC has revealed field and laboratory approaches leading to discovery of disease etiology that are now being applied to sporadic neurodegenerative disorders such as ALS beyond the Western Pacific region. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.

Preliminary seroprevalence study of neurotropic virus antibodies in Nodding syndrome.

Nodding syndrome (NS) is a mostly East African pediatric epileptiform encephalopathy of unknown etiology that shares some clinical features with measles-associated subacute sclerosing panencephalitis (SSPE) and progressive rubella panencephalitis. Two independent studies in northern Uganda identified an association between NS and prior measles infection, while an earlier study in South Sudan found an inverse association. We report preliminary serologic analyses of antibodies to measles (MV), rubella (RV), HSV-1, and CMV viruses in northern Ugandan children with NS and Household (HC) and Community (CC) Controls. Only MV-positive titers were significantly different (3-fold and > 2-fold) in NS relative to HC and HC + CC, respectively. While these results are consistent with greater prior measles infection in Ugandan persons with NS, further studies are needed to determine whether Measles virus (MV) plays any role in the etiology and pathogenesis of NS. Resolving this issue will be invaluable for the thousands of children at risk for this devastating yet often neglected condition.

The Role of Protein Adduction in Toxic Neuropathies of Exogenous and Endogenous Origin.

The peripheral (axonal) neuropathy associated with repeated exposure to aliphatic and aromatic solvents that form protein-reactive γ-diketones shares some clinical and neuropathological features with certain metabolic neuropathies, including type-II diabetic neuropathy and uremic neuropathy, and with the largely sub-clinical nerve damage associated with old age. These conditions may be linked by metabolites that adduct and cross-link neuroproteins required for the maintenance of axonal transport and nerve fiber integrity in the peripheral and central nervous system.