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MGMT, the gene coding for the DNA-repair protein O

This paper analyses documents on health and disease among Chamorro people during and after 333 years (1565–1898) of the Spanish claim to and occupation of Guam. Here, a complex neurodegenerative di...

COVID-19, the human primarily respiratory disease caused by the coronavirus SARS-CoV-2, commonly involves the nervous system, the effects of which may persist for many months. Post-acute sequelae of COVID-19 include relapsing and remitting neurological and neuropsychiatric symptoms that can affect children and adults, including those who had mild acute illness. Since longer-term adverse effects on the central and peripheral nervous system of COVID-19 cannot be excluded, patient and societal health trends should be monitored going forward. Urgent present needs include not only global immunization against SARS-CoV-2 but also the reestablishment of lapsed mass vaccination programs to prevent resurgence of other viral diseases (e.g., measles, polio) that can impact the nervous system. © Spencer P.S., Roman G., Buguet A., Guekht A., Reis J., 2021

Unknown environmental factors are thought to contribute to the etiology of sporadic forms of amyotrophic lateral sclerosis (ALS). Strong evidence supporting this view is found in the post-World War decline and disappearance of highincidence ALS in three Western Pacific populations that formerly utilized neurotoxic cycad seed as a traditional source of food and/or medicine. The principal toxins in cycads (cycasin) and in False Morel mushrooms (gyromitrin) generate methyl free radicals that damage DNA and cause mutation and uncontrolled division of cycling cells and degeneration of late-/postmitotic neurons. Since False Morels are scavenged for food in Finland, Russia, Spain, and USA, research studies are underway in Western Europe and USA to determine if the practice is associated with sporadic ALS.

The purpose of this article is to examine risk perception among some specific stakeholders, including international intergovernmental bodies, private western-based corporates, and among European public opinion surveys We also address concerns of the Russian Federation and the impact of China’s Belt and Road Initiative Perception of risks is key to policy decision-making and probably more important than risk assessment We offer a medico-scientific perspective based on factual evidence drawn mostly from official websites and publications Our first goal is to understand if sufficient attention is given to human health, disease prevention and control relative to economic and financial considerations Our second goal is to promote a translational and interprofessional approach to global risk prioritization by cooperation between the medico-scientific community and the financial-economic world To this end, we examine the benefits for the practice of economic risk assessment of engaging biomedical expertise focused on global environmental health Maintenance, expansion and sustainability of the human enterprise require health and wellness Осуществлен анализ представлений, связанных с рисками для здоровья человека, у определенных заинтересованных сторон, в том числе у международных межправительственных организаций, частных западных корпораций, которые отражаются в опросах общественного мнения в европейских странах Также проанализировано восприятие рисков здоровью населения в Российской Федерации, в том числе в связи с китайской инициативой «Один пояс, один путь» Представления о рисках и, следовательно, об иерархии рисков являются ключевыми факторами принятия решений при разработке политики и, возможно, даже более важны, чем оценка риска Авторы смотрят на перспективы анализа рисков как ученые - с позиций науки и медицины, с учетом существующих сведений, взятых большей частью с официальных веб-сайтов и публикаций Первая цель исследования - понять, достаточное ли внимание уделяется вопросам здоровья, предотвращения и контроля заболеваний по сравнению с экономическими и финансовыми вопросами Вторая цель - стимулировать применение поступательного и межпрофессионального подхода к анализу глобальных рисков через взаимодействие медико-научного сообщества и финансово-экономического мира С этих позиций изучены практические преимущества экономической оценки внешнесредовых рисков для здоровья населения с привлечением экспертов в области биомедицины Поддержание, расширение и устойчивое развитие всех аспектов человеческой жизнедеятельности подразумевает здоровье и благосостояние

Purpose To reexamine the etiology of a unique retinal pathology (linear and vermiform sub-retinal tubular structures) described among subjects with and without neurodegenerative disease in former high-incidence foci of Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) in Guam (USA) and the Kii peninsula of Honshu island (Japan). Methods Analysis of published and unpublished reports of 1) ALS/PDC and the retinal and cerebellar pathology associated therewith and 2) exogenous neurotoxic factors associated with ALS/PDC and the developing retina and cerebellum. Results ALS/PDC retinal and cerebellar pathology matches persistent retinal and cerebellar dysplasia found in laboratory animals given single in utero or postnatal systemic treatment with cycasin, the principal neurotoxic component in the seed of cycad plants traditionally used for food (Guam) or oral medicine (Kii-Japan), both of which have been linked to the human neurodegenerative disease. Conclusion ALS/PDC-associated retinal and cerebellar dysplasia could arise from in utero exposure to methylazoxymethanol, the genotoxic metabolite of cycasin that results from maternal ingestion of this azoxyglucoside. These results support the environmental toxic etiology of retinal and brain pathology in ALS/PDC.

The deleterious effects of aging on the brain remain to be fully elucidated. In the present study, proteomic changes of young (4-month) and aged (16-month) B6129SF2/J male mouse hippocampus and cerebral cortex were investigated by using nano liquid chromatography tandem mass spectrometry (NanoLC-ESI-MS/MS) combined with tandem mass tag (TMT) labeling technology. Compared with the young animals, 390 hippocampal proteins (121 increased and 269 decreased) and 258 cortical proteins (149 increased and 109 decreased) changed significantly in the aged mouse. Bioinformatic analysis indicated that these proteins are mainly involved in mitochondrial functions (FIS1, DRP1), oxidative stress (PRDX6, GSTP1, and GSTM1), synapses (SYT12, GLUR2), ribosome (RPL4, RPS3), cytoskeletal integrity, transcriptional regulation, and GTPase function. The mitochondrial fission-related proteins FIS1 and DRP1 were significantly increased in the hippocampus and cerebral cortex of the aged mice. Further results in the hippocampus showed that ATP content was significantly reduced in aged mice. A neurotrophin brain-derived neurotrophic factor (BNDF), a protein closely related with synaptic plasticity and memory, was also significantly decreased in the hippocampus of the aged mice, with the tendency of synaptic protein markers including complexin-2, synaptophysin, GLUR2, PSD95, NMDAR2A, and NMDAR1. More interestingly, 8-hydroxydeoxyguanosine (8-OHdG), a marker of DNA oxidative damage, increased as shown by immunofluorescence staining. In summary, we demonstrated that aging is associated with systemic changes involving mitochondrial dysfunction, energy reduction, oxidative stress, loss of neurotrophic factor, synaptic proteins, and ribosomal proteins, as well as molecular deficits involved in various physiological/pathological processes.

The design used to source animals for translocation and captive breeding programmes can strongly influence sampling results and outcomes. To date, no trapping design has been specifically directed at maximizing genetic diversity of individuals for use in such programmes. Using genetic and demographic data, we investigated the spatial structure of critically endangered woylie (Bettongia penicillata ogilbyi ) populations for developing a spatial trapping design that would return a genetically representative cohort of animals by taking advantage of the dispersal behaviour of the species. Using microsatellite markers, we tested our design against more conventional trapping approaches and determined that animals captured under our spatial design were less related than animals captured using grid or standard transect designs. We clearly show that incorporating the target species’ ecology (e.g. dispersal patterns) in the capture design will improve the genetic differences (through reduced relatedness) between harvested individuals. This study sets out a practical approach that can significantly improve potential conservation outcomes. This approach is applicable to all species that have a predictable dispersal pattern.

It is generally assumed that population supplementation will improve the genetic diversity of the recipient populations. However, the genetic outcomes of supplementations are rarely tested. We used population modelling to predict how the supplementation programme in a translocated Woylie (Bettongia penicillata ogilbyi) population influences their genetic makeup. Our model projections were then compared against real genetic data collected before and after supplementation, to determine whether or not supplementation was effective at increasing genetic diversity and to test the accuracy of the model. Post‐supplementation genetic diversity parameters (heterozygosity and allelic richness) were significantly higher following supplementation, and there was no significant difference from those predicted by the model. These results are encouraging; however, many factors can influence supplementation outcomes and we recommend ongoing monitoring in translocated populations to ensure that population trends are on target.

The Common Rock Rat Zyzomys argurus is an abundant small- to medium-sized Murid rodent that is endemic to Australia. It is a nocturnal mammal with a mostly herbivorous diet. This species is native to the wet/dry tropics of Northern Australia and can be identified from other rock rats on the basis of its small size and its tail length (which is at least equivalent to its head-body length). Here, we describe the complete mitochondrial genome of Z. argurus and compare it to other Rodentia. The Z. argurus circular mitogenome was 16,261 bp and contained 13 protein-coding genes, two rRNA genes, 22 tRNAs and a control region (D-loop) of 859 bp. Phylogenetic analysis of selected, published sequenced mitogenomes reveal it is most closely related to the Lakeland Downs mouse Leggadina lakedownensis in the order Rodentia.

In this announcement, we report the complete mitogenome of the vulnerable Crest-tailed Mulgara (Dasycercus cristicauda) (Krefft, 1867). The mitogenome was 17,085 bp in length and contained 13 protein-coding genes, two rRNA genes, 22 tRNAs and a 1583 bp variable control region (D-loop). The features of the D. cristicauda mitogenome are consistent with other vertebrate mitogenomes but, in contrast to other marsupials, appears to contain a functional tRNA-Lysine with a UUU anticodon. Phylogenetic analysis of available entire mitogenomes reveals it forms a cluster with other marsupials in the Dasyuromorphia order within the Australidelphian clade, being most closely related to the Northern Quoll and the Tasmanian Devil.

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.

Nodding syndrome (NS) is a progressive encephalopathy of children and adolescents characterized by seizures, including periodic vertical head nodding. Epidemic NS, which has affected parts of East Africa, appears to have clinical overlap with sub-Saharan Nakalanga syndrome (NLS), a brain disorder associated with pituitary dwarfism that appears to have a patchy distribution across sub-Sahara. Clinical stages of NS include inattention and blank stares, vertical head nodding, convulsive seizures, multiple impairments, and severe cognitive and motorsystem disability, including features suggesting parkinsonism. Head nodding episodes occur in clusters with an electrographic correlate of diffuse high-amplitude slow waves followed by an electrodecremental pattern with superimposed diffuse fast activity. Brain imaging reveals differing degrees of cerebral cortical and cerebellar atrophy. Brains of NS-affected children with mild frontotemporal cortical atrophy display neurofibrillary pathology and dystrophic neurites immunopositive for tau, consistent with a progressive neurodegenerative disorder. The etiology of NS and NLS appears to be dominated by environmental factors, including malnutrition, displacement, and nematode infection, but the specific cause is unknown.

Polyandry is a commonly utilized strategy in mammalian reproductive systems, where females engage in mating with multiple males to increase either the genetic diversity or quality of their offspring. Some species also exhibit male semelparity, a peculiar life‐history trait where all or most males within a population begin to die following mating. The northern quoll (Dasyurus hallucatus) possesses both of these reproductive adaptations, and females of this species may produce up to eight young in a single litter. Here we aimed to quantify whether there was any difference in female quolls’ choice of male sires between two genetically distinct populations located in the Pilbara region of Western Australia (one mainland‐dwelling and one island‐dwelling population). The total parentage exclusion probability was 0.9999 for excluding a candidate parent from parentage, given the genotype of a known mother. Overall, we found that every litter had young resulting from multiple males. In some litters, a different male fathered every offspring. Thus, northern quolls demonstrated a greater level of polyandry than has previously been detected in marsupials. Furthermore, females from the less genetically diverse island population exercised mate choice and preferentially bred with males that were, on average, 20% smaller than a different male randomly sampled from the island. There was no detectable difference with regard to male sire body size in the mainland population, indicating a difference of selective pressures for the two populations.

Lathyrism is a central motor system disorder recognized since antiquity resulting from prolonged dietary dependence on the grasspea (Lathyrus sativus). The neuropathology underlying the characteristic spastic paraparesis of lathyrism is sketchy. Described here is a landmark but little-known Spanish-language neuropathological study of two patients with lathyrism of recent onset. Due to erroneous interpretations of Filimonov's influential work in 1926, it was assumed that spastic paraparesis of lathyrism was explained by destruction of Betz's pyramidal cells in the motor cortex. Contrary to present understanding, Betz cells and anterior horn cells were preserved, and pathological findings dominated by myelin loss were largely limited to pyramidal tracts in the lumbar cord. Thickening of the adventitia of capillaries and arterioles, together with proliferation of perivascular astrocytes, was found along the length of the spinal cord. Oliveras de la Riva proposed that the segmental spinal pathology arose because distal regions of elongate pyramidal tract axons are distant from their trophic center in the motor cortex, a view not far from the current distal axonopathy concept of lathyrism. In addition, we review the historical circumstances of Filimonov's work in Russia, a summary of the epidemic of lathyrism in Spain following its Civil War (1936-1939), and some historical aspects of the Cajal Institute in Madrid, where Oliveras de la Riva's work was carried out under the supervision of Fernando de Castro, one of Cajal's favorite students.

N-Nitrosamines are drinking water disinfection byproducts that pose a high carcinogenic risk. We hypothesized that raw water treatment processes influence the types and concentrations of nitrosamines in drinking water, thereby posing differential health risks. We compared the finished water of two water treatment plants (WTP-A, WTP-B) serving Shanghai, China. Both plants use the Qingcaosha reservoir as a water source to generate drinking water with conventional but distinct treatment processes, namely preoxidation with sodium hypochlorite (WTP-A) vs ozone (WTP-B). Average nitrosamine concentrations, especially that of the probable human carcinogen (2A) N-nitrosodimethylamine, were higher in finished (drinking) water from WTP-A (35.83 ng/L) than from WTP-B (5.07 ng/L). Other differences in mean nitrosamines in drinking water included N-nitrosodipropylamine (42.62 ng/L) and N-nitrosomethylethylamine (26.73 ng/L) in WTP-A in contrast to N-nitrosodiethylamine (7.26 ng/L) and N-nitrosopyrrolidine (59.12 ng/L) in WTP-B. The estimated adult cancer risk from exposure to mixed nitrosamines was 1.83 times higher from WTP-A than from WTP-B drinking water. Children exposed to nitrosamines had a significantly higher cancer risk than adults ( p < 0.05). Disease burden exceeded 106 person-years. Taken together, these data suggest that use of ozone in the preoxidation step can reduce nitrosamine formation in drinking water and thereby lower the population cancer health risk.

We address the impact of the tropical environment on the human nervous system using the multifaceted approach characteristic of environmental neurology. First, environmental factors are examined according to their nature (physical, chemical and biological) and in relation to human activity and behavior. Some factors are specific to the tropics (climate and infections), while others are non-specific (chemicals, human communities and their way of life). Second, we examine the major role of human adaptation to the success of Homo sapiens, with emphasis on the linkage between thermoregulation and sleep-wake regulation. Third, we examine the performance of environmental neurology as a clinical discipline in tropical climates, with focus on the diagnostic and therapeutic challenges posed by human African trypanosomiasis. Finally, the prevention, early detection and monitoring of environmental neurological diseases is examined, as well as links with political and economic factors. In conclusion, practitioners of environmental neurology seek a global, multidisciplinary and holistic approach to understanding, preventing and treating neurological disorders within their purview. Environmental neurology integrates an expanded One Health concept by linking health and wellness to the interaction of plants, animals, humans and the ecosystem. Recent epidemics and the current COVID-19 pandemic exemplify the need for worldwide action to protect human health and biodiversity.

The Ghost bat Macroderma gigas is a monotypic bat species that is endemic to northern Australia and named on the basis of the large size of its partially conjoined ears. It is the only carnivorous bat found in Australia and its conservation status is currently listed as Vulnerable. Here, we describe the complete mitochondrial genome of M. gigas and compare it to other vertebrates. The M. gigas circularized mitogenome was 16,661 bp and contained 13 protein-coding genes, two rRNA genes, 22 tRNAs and a control region (D-loop) of 1228 bp. Phylogenetic analysis of available entire mitogenomes reveals that Macroderma gigas is most closely related to the Indian false vampire bat Megaderma lyra in the family Megadermatidae (false vampire bats).

Between 1990 and 2018, 14 cases of amyotrophic lateral sclerosis (ALS) were diagnosed in residents of, and in visitors with second homes to, a mountainous hamlet in the French Alps. Systematic investigation revealed a socio-professional network that connected ALS cases. Genetic risk factors for ALS were excluded. Several known environmental factors were scrutinized and eliminated, notably lead and other chemical contaminants in soil, water or home-grown vegetation used for food, radon and electromagnetic fields. Some lifestyle-related behavioral risk factors were identified: Prior to clinical onset of motor neuron disease, some patients had a high degree of athleticism and smoked tobacco. Recent investigations on site, based on a new hypothesis, showed that all patients had ingested wild mushrooms, notably poisonous False Morels. Half of the ALS cohort reported acute illness following Gyromitra gigas mushroom consumption. This finding supports the hypothesis that genotoxins of fungal origin may induce motor neuron degeneration.

Many Australian mammal species now only occur on islands and fenced mainland havens free from invasive predators. The range of one species, the banded hare-wallaby (Lagostrophus fasciatus), had contracted to two offshore islands in Western Australia. To improve survival, four conservation translocations have been attempted with mixed success, and all occurred in the absence of genetic information. Here, we genotyped seven polymorphic microsatellite markers in two source (Bernier Island and Dorre Island), two historic captive, and two translocated L. fasciatus populations to determine the impact of multiple translocations on genetic diversity. Subsequently, we used population viability analysis (PVA) and gene retention modelling to determine scenarios that will maximise demographic resilience and genetic richness of two new populations that are currently being established. One translocated population (Wadderin) has undergone a genetic bottleneck and lost 8.1% of its source population&rsquo, s allelic diversity, while the other (Faure Island) may be inbred. We show that founder number is a key parameter when establishing new L. fasciatus populations and 100 founders should lead to high survival probabilities. Our modelling predicts that during periodic droughts, the recovery of source populations will be slower post-harvest, while 75% more animals&mdash, about 60 individuals&mdash, are required to retain adequate allelic diversity in the translocated population. Our approach demonstrates how genetic data coupled with simulations of stochastic environmental events can address central questions in translocation programmes.

IMPORTANCE: The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, is serious and has the potential to become an epidemic worldwide. Several studies have described typical clinical manifestations including fever, cough, diarrhea, and fatigue. However, to our knowledge, it has not been reported that patients with COVID-19 had any neurologic manifestations. OBJECTIVE: To study the neurologic manifestations of patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective, observational case series. Data were collected from January 16, 2020, to February 19, 2020, at 3 designated special care centers for COVID-19 (Main District, West Branch, and Tumor Center) of the Union Hospital of Huazhong University of Science and Technology in Wuhan, China. The study included 214 consecutive hospitalized patients with laboratory-confirmed diagnosis of severe acute respiratory syndrome coronavirus 2 infection. MAIN OUTCOMES AND MEASURES: Clinical data were extracted from electronic medical records, and data of all neurologic symptoms were checked by 2 trained neurologists. Neurologic manifestations fell into 3 categories: central nervous system manifestations (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure), peripheral nervous system manifestations (taste impairment, smell impairment, vision impairment, and nerve pain), and skeletal muscular injury manifestations. RESULTS: Of 214 patients (mean [SD] age, 52.7 [15.5] years; 87 men [40.7%]) with COVID-19, 126 patients (58.9%) had nonsevere infection and 88 patients (41.1%) had severe infection according to their respiratory status. Overall, 78 patients (36.4%) had neurologic manifestations. Compared with patients with nonsevere infection, patients with severe infection were older, had more underlying disorders, especially hypertension, and showed fewer typical symptoms of COVID-19, such as fever and cough. Patients with more severe infection had neurologic manifestations, such as acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]), impaired consciousness (13 [14.8%] vs 3 [2.4%]), and skeletal muscle injury (17 [19.3%] vs 6 [4.8%]). CONCLUSIONS AND RELEVANCE: Patients with COVID-19 commonly have neurologic manifestations. During the epidemic period of COVID-19, when seeing patients with neurologic manifestations, clinicians should suspect severe acute respiratory syndrome coronavirus 2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent further transmission.

IntroductionProgressive distal symmetrical axonal neuropathy, a complication of diabetes mellitus (DM), has an unknown cause. Normal physiological metabolism and diabetic dysmetabolism are associated with the generation of γ-diketones. γ-Diketones form pyrroles with protein amines, notably with axonal proteins required for the maintenance of nerve fiber integrity, especially elongate, large-diameter peripheral nerve fibers innervating the extremities. We tested the hypothesis that neuropathy-associated γ-diketone pyrroles are elevated in DM.Research design and methodsWe measured the urinary concentration of γ-diketone pyrroles in age-matched and gender-matched elderly (60–84 years) persons with (n=267) or without (n=267) indicators of DM based in a community population (9411 community older adults aged ≥60 years) in Shenzhen city, Guangdong, China. We used statistical methods, including a generalized linear model, multivariate logistic regression analysis and restricted cubic splines, to assess linear and nonlinear relationships between urinary γ-diketone pyrroles and indicators of DM.ResultsCompared with healthy controls, those with DM had significantly higher levels of fasting blood glucose, glycated hemoglobin A1c, urinary ketone bodies and urinary γ-diketone pyrroles. The median concentration of urinary γ-diketone pyrrole adducts was significantly higher (pConclusionsDiabetic dysmetabolism includes increased generation and excretion of neuropathy-associated γ-diketone pyrroles. These findings form the foundation for studies to test whether γ-diketone pyrrole concentration correlates with quantitative sensory (vibration and temperature) and electrodiagnostic testing.

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.

Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-dementia Complex (ALS/PDC) is a disappearing neurodegenerative disease in three former high-incidence foci of Guam-USA, Papua-Indonesia and Kii Peninsula, Honshu Island, Japan. The latter includes two distinct ALS/PDC-affected regions (Hohara and Kozagawa), where the disorder is known as Muro disease. In Hohara, oral exposure to plant (cycad) neurotoxins used in traditional medical practice has been linked previously to Muro disease. We report new observations that link Kampō medicine to Muro disease in the southern Kozagawa focus. Oral exposure to cycad seed toxins is associated with all three foci of Western Pacific ALS/PDC. Keywords: Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex, Kii peninsula, Honshu, Japan, Traditional/folk medical practice, Cycad seed, Sotetsu

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 β-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.

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 (Aβ1–42), 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.

Insular populations are particularly vulnerable to the effects of stochastic events, epidemics, and loss of genetic diversity due to inbreeding and genetic drift. The development of successful management options will require accurate baseline data, establishment of clear objectives, and finally monitoring and implementation of corrective measures, if and when required. This study assessed management options for the genetic rehabilitation of highly inbred woylies obtained from wildlife rehabilitation centers. The study generated genetic data for the woylie Bettongia penicillata from a conservation reserve and calculated measures of genetic diversity and individual relatedness. These data were fed into a population viability analysis (PVA) to test genetic outcomes in relation to different management actions. We demonstrated that a careful selection of the founder cohort produced a population with an expected heterozygosity of ∼70% for a window of approximately 10 years. A proposal to increase the size of the reserve available to the colony was shown to almost double the time at which the colony would retain heterozygosity levels of ≥ 70%. Additionally, developing a regular program of supplementation of unrelated woylies would result in a further improvement in their genetic value. This study demonstrated how the application of molecular techniques in combination with PVA can be beneficial for the management of rehabilitated wildlife otherwise considered of little conservation value. This approach can be applied to the management of breeding programs, but also to small, closed populations such as those found on islands, fenced enclosures, insurance populations, and in zoological collections.

Invasive species are a leading cause of animal extinctions. It is difficult to eradicate established and widespread populations of invaders, so we need novel approaches to reduce their impact on imperilled wildlife. In Australia, the toxic cane toad Rhinella marina has caused local extinctions of northern quolls Dasyurus hallucatus. Quolls lack immunity to toad toxins, and die after attacking adult toads. Using a novel approach, we modified quoll behaviour by feeding them small, non-lethal toads laced with a nausea-inducing chemical. Quolls that consumed the baits became ill, and subsequently ignored toads. We reintroduced these ‘toad-smart’ quolls to Kakadu National Park to determine whether aversion training could be an effective conservation tool. To measure the success of our innovation, it was important that reintroduced quolls survived to reproduce in a toad-infested landscape. We used parentage analysis to confirm the maternity of 12 wild-born quolls. ‘Toad-smart’ female quolls not only survived to reproduce, but their children and grandchildren survived as well. Training a single cohort of quolls yielded a long-term conservation benefit, without requiring continued conservation effort or eradication of the toxic invader.

The ghost bat (Macroderma gigas) is endemic to Australia but is under threat, with scarce information available on the genetic health of remaining populations. Here, we develop molecular assays for microsatellite genotyping and molecular sexing of non-invasive samples as a genetic monitoring tool to identify individuals, measure genetic diversity and investigate spatial and temporal patterns of habitat use by ghost bats. We identified novel microsatellites through high-throughput sequencing on the Illumina MiSeq platform. Of 48 loci tested, six markers were added to five previously developed microsatellite loci. We developed three Y-linked (DDX3Y, Zfy and SRY) and one X-linked markers (Zfx) to enable molecular identification of sex. To assess performance, all 11 microsatellite and four sex-linked markers were amplified in three multiplex reactions in 160 M. gigas faecal samples from the Pilbara region, Western Australia. The combined markers offered a high level of individual discrimination (PIDsibs = 0.00002) and we detected 19 bats in total (11 males, 4 females and 4 sex undetermined). The number of alleles per locus ranged from 5 to 14 and the average observed and expected heterozygosity across loci were Ho = 0.735 (0.58–0.91) and uHe = 0.785 (0.59–0.89) respectively. Our molecular assays allowed identification of individuals from faecal samples at multiple time points and spatial locations and enabled us to elucidate patterns of habitat usage at the study site. This study highlights the value of our molecular assays as a potential capture-mark-recapture technique for population monitoring for this species.