Amyotrophic Lateral Sclerosis And Parkinsonism-dementia Complex Research Articles

Microglia-containing cerebral organoids derived from induced pluripotent stem cells for the study of neurological diseases

Microglia play an important role in neuroinflammation and neurodegeneration. Here, we report an approach for generating microglia-containing cerebral organoids derived from human pluripotent stem cells involving the supplementation of growth factors (FGF, EGF, heparin) and 10% CO2 culture conditions. Usingthis platform, Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS-PDC) cerebral organoids were generated from patient-derived induced pluripotent stem cells (iPSCs). These ALS-PDC-affected organoids had more reactive astrocytes and M1 microglia, and had fewer M2 microglia than their unaffected counterparts, leading to impaired microglia-mediated phagocytosis. RNA-seq analysis of ALS-PDC and control organoids indicated that the most significant changes were microglia- and astrocyte-related genes (IFITM1/2, TGF-β, and GFAP). The most significantly downregulated pathway was type I interferon signaling. Interferon-gamma supplementation increased IFITM expression, enhanced microglia-mediated phagocytosis, and reduced beta-amyloid accumulation in ALS-PDC-affected network. The results demonstrated the feasibility of using microglia-containing organoids for the study of neurodegenerative diseases.

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 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.

Lytico-bodig in Guam: Historical links between diet and illness during and after Spanish colonization

ABSTRACT 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 disease—known locally as lytico-bodig and medically as amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC)—reached hyperendemic proportions in the mid-twentieth century but then declined and is now disappearing. A tau-dominated polyproteinopathy, clinical phenotypes included amyotrophic lateral sclerosis (ALS or lytico), atypical parkinsonism with dementia (P-D or bodig), and dementia alone. A plausible etiology for lytico-bodig is consumption of flour derived from the incompletely detoxified seed of Cycas micronesica (fadang in Chamorro; Federico in Spanish), a poisonous gymnosperm that survives climatic extremes that can affect the island. Traditional methods for safe consumption appear to have been lost over the course of time since governors Francisco de Villalobos (1796–1862) and Felipe de la Corte (1855–1866) proposed banning consumption in view of its acute toxic effects. A death certificate issued in 1823 might suggest ALS/PDC in people dying with disability or impedidos, and premature aging and a short life was linked to food use of fadang in the mid-1850s (Guam Vital Statistics Report, 1823). During the Japanese occupation of Guam (1941–1944), Chamorro people took refuge in the jungle for months, where they relied on insufficiently processed fadang as a staple food. After World War II, traditional foods and medicines were subsequently replaced as islanders rapidly acculturated to North American life.

Kampō medicine and Muro disease (Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex): Postscript and Historical Footnote.

Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-dementia Complex (ALS/PDC) is a disappearing neurodegenerative disease in three former high-incidence foci of the U.S. territory of Guam, Papua-Indonesia (New Guinea) and Kii Peninsula, Honshu Island, Japan (Muro disease). We report additional data that associate medicinal use of cycad seed to Muro disease in the southern Kozagawa focus of ALS/PDC. In the other two ALS/PDC-affected populations, cycad seed was used as a traditional topical medicine in New Guinea and Guam and, additionally, for food on Guam.

Etiology of Retinal and Cerebellar Pathology in Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex.

PurposeTo 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).MethodsAnalysis 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.ResultsALS/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.ConclusionALS/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.

Brain Transcriptome Analysis Links Deficiencies of Stress-Responsive Proteins to the Pathomechanism of Kii ALS/PDC.

Amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC) is a unique endemic neurodegenerative disease, with high-incidence foci in Kii Peninsula, Japan. To gather new insights into the pathological mechanisms underlying Kii ALS/PDC, we performed transcriptome analyses of patient brains. We prepared frozen brains from three individuals without neurodegenerative diseases, three patients with Alzheimer’s disease, and 21 patients with Kii ALS/PDC, and then acquired microarray data from cerebral gray and white matter tissues. Microarray results revealed that expression levels of genes associated with heat shock proteins, DNA binding/damage, and senescence were significantly altered in patients with ALS/PDC compared with healthy individuals. The RNA expression pattern observed for ALS-type brains was similar to that of PDC-type brains. Additionally, pathway and network analyses indicated that the molecular mechanism underlying ALS/PDC may be associated with oxidative phosphorylation of mitochondria, ribosomes, and the synaptic vesicle cycle; in particular, upstream regulators of these mechanisms may be found in synapses and during synaptic trafficking. Furthermore, phenotypic differences between ALS-type and PDC-type were observed, based on HLA haplotypes. In conclusion, determining the relationship between stress-responsive proteins, synaptic dysfunction, and the pathogenesis of ALS/PDC in the Kii peninsula may provide new understanding of this mysterious disease.

Kampō medicine and Muro disease (Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex).

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.

Hypothesis: Etiologic and Molecular Mechanistic Leads for Sporadic Neurodegenerative Diseases Based on Experience With Western Pacific ALS/PDC.

Seventy years of research on Western Pacific amyotrophic lateral sclerosis and Parkinsonism-dementia Complex (ALS/PDC) have provided invaluable data on the etiology, molecular pathogenesis and latency of this disappearing, largely environmental neurodegenerative disease. ALS/PDC is linked to genotoxic chemicals (notably methylazoxymethanol, MAM) derived from seed of the cycad plant (Cycas spp.) that were used as a traditional food and/or medicine in all three disease-affected Western Pacific populations. MAM, nitrosamines and hydrazines generate methyl free radicals that damage DNA (in the form of O6-methylguanine lesions) that can induce mutations in cycling cells and degenerative changes in post-mitotic cells, notably neurons. This paper explores exposures to naturally occurring and manmade sources of nitrosamines and hydrazines in association with sporadic forms of ALS (with or without frontotemporal degeneration), progressive supranuclear palsy, and Alzheimer disease. Research approaches are suggested to examine whether these associations might have etiological significance.Lay SummaryUnknown environmental exposures are thought to be risk factors for non-inherited forms of certain progressive brain diseases, such as sporadic forms of amyotrophic lateral sclerosis (sALS), progressive supranuclear palsy (sPSP), and Alzheimer's disease (sAD). Related progressive and fatal brain disorders coalesce in a single neurodegenerative disease of largely environmental origin (ALS-Parkinsonism-dementia Complex) that has affected three genetically distinct populations residing in islands of the Western Pacific region. Prolonged study of this prototypical neurodegenerative disease has provided invaluable information on the probable environmental cause (specific chemical genotoxins) and molecular mechanisms (unrepaired nerve cell DNA-damage) by which brain degeneration begins, evolves and, years or decades later, clinical signs appear, and progress. This information is used as a foundation to explore whether chemically related genotoxins (nitrosamines, hydrazines) are possible risk factors for sALS, sPSP, and sAD. Methods to test this hypothesis in the field and laboratory are proposed.

β-N-methylamino-l-alanine analysis in the brains of patients with Kii ALS/PDC.

The Kii Peninsula of Japan and the island of Guam are known as high-incidence areas of amyotrophic lateral sclerosis and parkinsonism–dementia complex (ALS/PDC). The disorder is clinically characterized by a variable presentation of parkinsonism, dementia, and motor neuron symptoms and pathologically by tau protein deposits in the CNS.1 Both genetic and environmental factors are implicated in ALS/PDC pathogenesis. Exposure to β-N-methylamino-l-alanine (BMAA), a neurotoxin produced by cyanobacteria, has been proposed as a risk factor for ALS/PDC in Guam.2 It is not known whether Kii ALS/PDC shares the same etiology as Guam ALS/PDC. To address these issues, we conducted BMAA analyses of brain samples from 5 patients with Kii ALS/PDC using high-performance liquid chromatography (HPLC) and liquid chromatography–tandem mass spectrometry (LC/MS/MS). Acknowledgment: The authors thank Junko Karita for clerical assistance and Enago ( [ enago.jp ][1] ) for the English language review. The authors also thank the H.L. Castle Foundation, the W. F. Coulter Foundation, and the Margaret Q. Landenberger Foundation, as well as C. Childs, K. Farkas, and L. Atherton for research funding. [1]: http://www.enago.jp/

L-β-N-methylamino-l-alanine (BMAA) nitrosation generates a cytotoxic DNA damaging alkylating agent: An unexplored mechanism for neurodegenerative disease

BackgroundL-β-N-methylamino-l-alanine (BMAA) is a non-proteinic amino acid, that is neurotoxic in vitro and in animals, and is implicated in the causation of amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC) on Guam. Given that natural amino acids can be N-nitrosated to form toxic alkylating agents and the structural similarity of BMAA to other amino acids, our hypothesis was that N-nitrosation of BMAA might result in a toxic alkylating agent, providing a novel mechanistic hypothesis for BMAA action. FindingsWe have chemically nitrosated BMAA with sodium nitrite to produce nitrosated BMAA (N-BMAA) which was shown to react with the alkyl-trapping agent, 4-(p-nitrobenzyl)pyridine, cause DNA strand breaks in vitro and was toxic to the human neuroblastoma cell line SH-SY5Y under conditions in which BMAA itself was minimally toxic. ConclusionsOur results indicate that N-BMAA is an alkylating agent and toxin suggesting a plausible and previously unrecognised mechanism for the neurotoxic effects of BMAA.

Seeking environmental causes of neurodegenerative disease and envisioning primary prevention

Pathological changes of the aging brain are expressed in a range of neurodegenerative disorders that will impact increasing numbers of people across the globe. Research on the causes of these disorders has focused heavily on genetics, and strategies for prevention envision drug-induced slowing or arresting disease advance before its clinical appearance. We discuss a strategic shift that seeks to identify the environmental causes or contributions to neurodegeneration, and the vision of primary disease prevention by removing or controlling exposure to culpable agents. The plausibility of this approach is illustrated by the prototypical neurodegenerative disease amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC). This often-familial long-latency disease, once thought to be an inherited genetic disorder but now known to have a predominant or exclusive environmental origin, is in the process of disappearing from the three heavily affected populations, namely Chamorros of Guam and Rota, Japanese residents of Kii Peninsula, Honshu, and Auyu and Jaqai linguistic groups on the island of New Guinea in West Papua, Indonesia. Exposure via traditional food and/or medicine (the only common exposure in all three geographic isolates) to one or more neurotoxins in seed of cycad plants is the most plausible if yet unproven etiology. Neurotoxin dosage and/or subject age at exposure might explain the stratified epidemic of neurodegenerative disease on Guam in which high-incidence ALS peaked and declined before that of PD, only to be replaced today by a dementing disorder comparable to Alzheimer’s disease. Exposure to the Guam environment is also linked to the delayed development of ALS among a subset of Chamorro and non-Chamorro Gulf War/Era veterans, a summary of which is reported here for the first time. Lessons learned from this study and from 65 years of research on ALS-PDC include the exceptional value of initial, field-based informal investigation of disease-affected individuals and communities, the results of which can provide an invaluable guide to steer cogent epidemiological and laboratory-based research.

Western Pacific ALS-PDC: a prototypical neurodegenerative disorder linked to DNA damage and aberrant proteogenesis?

Western Pacific ALS-PDC: a prototypical neurodegenerative disorder linked to DNA damage and aberrant proteogenesis?

Amyotrophic lateral sclerosis of Guam: the nature of the neuropathological findings.

To elucidate the fundamental differences and similarities of the neuropathological features and etiopathogenesis of the amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) of Guam, we conducted a topographic, quantitative and histological investigation of tau-containing neurons, neurofibrillary tangles (NFTs), Bunina bodies and ubiquitinated inclusion bodies in 27 non-ALS non-PDC Guamanian subjects, as well as 10 Guam ALS patients, 28 PDC patients, and 5 patients with combined ALS and PDC (ALS-PDC). The topographic distribution of NFTs was basically the same in each disease and also in the non-ALS non-PDC group. There were relatively few, if any, NFTs in non-ALS non-PDC subjects and ALS patients, but there were many, especially in the frontal and temporal cortex, in Guam PDC and ALS-PDC patients. The histological and ultrastructural features of Bunina bodies in Guam ALS and ALS-PDC patients were similar to those reported in classic ALS. The ratio of occurrence of the inclusion in Guam ALS and ALS-PDC patients was similar to that reported so far in classic ALS. Ubiquitinated skein-like inclusion bodies were observed in the spinal anterior horn cells in Guam ALS and ALS-PDC patients. These findings indicate that classic ALS does exist on Guam, that NFTs in Guam ALS patients are merely a background feature widely dispersed in the population, that the mechanism of neuronal degeneration of Guam ALS is basically different from that of PDC, and that Guam ALS occurs initially are classic ALS.