Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the middle of this century, a remarkable concentration of cases of neurodegenerative disease(s), referred to as amyotrophic lateral sclerosis and Parkinson-dementia complex (ALS/PDC), has been recognized among Chamorro natives of Guam. Intense investigations over the last 4 decades have failed to determine the etiology of these invariably fatal diseases. Over the same time period, the incidence of ALS has decreased dramatically, the incidence of PDC has decreased, but to a lesser degree, and age at onset has shifted to a later age by about 1 decade. Almost 50% of demented patients present without the classical Parkinsonian features of PDC, and the morphological picture has changed. Results of past and present research initiatives are reviewed.
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PMID:Neuroepidemiologic research initiatives on Guam: past and present. 1054 80

Filamentous tau aggregates are hallmarks of tauopathies, e.g., frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC). Since FTDP-17 tau gene mutations alter levels/functions of tau, we overexpressed the smallest human tau isoform in the CNS of transgenic (Tg) mice to model tauopathies. These mice acquired age-dependent CNS pathology similarto FTDP-17 and ALS/PDC, including insoluble, hyperphosphorylated tau and argyrophilic intraneuronal inclusions formed by tau-immunoreactive filaments. Inclusions were present in cortical and brainstem neurons but were most abundant in spinal cord neurons, where they were associated with axon degeneration, diminished microtubules (MTs), and reduced axonal transport in ventral roots, as well as spinal cord gliosis and motor weakness. These Tg mice recapitulate key features of tauopathies and provide models for elucidating mechanisms underlying diverse tauopathies, including Alzheimer's disease (AD).
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PMID:Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. 1059 24

The patient was 68 year-old woman with an 8-year history of parkinsonism which was followed by psychiatric symptoms and neurogenic amyotrophy 5 years after the onset. She had a family history of parkinsonism associated with dementia in all of her three siblings. They grew up in Hobara village, a focus of amyotrophic lateral sclerosis (ALS) in the Kii Peninsula of Japan, in their childhood. Their parents were neither consanguineous nor natives of the Kii Peninsula. The brain weight was 1,040 g, and there were mild frontal lobe atrophy, moderate atrophy of pes hippocampi, decoloration of the substantia nigra and locus ceruleus, and anterior spinal root atrophy. The microscopic examinations revealed degeneration of CA 1 portion of the hippocampus to parahippocampal gyrus, substantia nigra, locus ceruleus and spinal anterior horn with Bunina body. The spinal pyramidal tracts also degenerated mildly. The neurofibrillary tangles (NFT) were observed in the cerebral cortex, especially in the cortices through hippocampus to lateral occipitotemporal gyri, basal nucleus of Meynert, basal ganglia, thalamus, substantia nigra and widespread regions of the central nervous system through the brainstem to the spinal cord including the nucleus of Onufrowicz. In spite of a few amount of the senile plaques in the cerebral cortex and Lewy bodies in the substantia nigra and locus ceruleus, abundant NFT distributed mainly in the third layer of the cerebral cortex, which is the characteristic finding of amyotrophic lateral sclerosis/Parkinsonism-dementia Complex (ALS/PDC) in the island of Guam. Thus this was verified ALS/PDC case outside the Guam island. The high incidence of neurological disease in her siblings and their history of living in the focus region in childhood suggest the genetic factor of ALS/PDC which is sensitive to certain environmental agents in the early stage of the life.
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PMID:[An autopsy case of amyotrophic lateral sclerosis/parkinsonism-dementia complex with family history and living history in the Kii Peninsula focus]. 1068 33

High-affinity glutamate transporters ensure termination of glutamatergic neurotransmission and keep the synaptic concentration of this amino acid below excitotoxic levels. However, neuronal glutamate transporters, EAAC1 and EAAT4, are located outside the synaptic cleft and contribute less significantly to the glutamate uptake in the brain than two astroglial transporters, GLAST and GLT1. Aberrant functioning of the glutamate uptake system seems to be linked to some neurodegenerative disorders (eg amyotrophic lateral sclerosis, ALS). Expression of glutamate transporters is differentially regulated via distinct cellular mechanisms. GLT1, which is expressed at very low levels in cultured astrocytes, is strongly induced in the presence of neurons. The present immunocytochemical data provide further evidence that neuronal soluble factors, rather than physical contact between neurons and glia, determine the induction of GLT1 in astrocytes. This effect is apparently mediated by yet undefined growth factor(s) via the tyrphostin-sensitive receptor tyrosine kinase (RTK) signalling, that in turn, supports the downstream activation of p42/44 MAP kinases and the CREM and ATF-1 transcription factors. RTK-independent simultaneous activation of the CREB transcription factor suggests a possible involvement of complementary pathway(s). Neuronal soluble factors do not affect expression of GLAST, but induce supporting machinery for differential regulation of GLAST via the astroglial metabotropic glutamate receptors, mGluR3 and mGluR5. Thus, long-term treatment with the group I mGluR agonist, DHPG, causes down-regulation of GLAST, whereas the group II agonist, DCG-IV, has an opposite effect on the expression of GLAST in astrocytes. However, in BT4C glioma cells glutamate or other transportable substrates (D-aspartate and L-2,4-trans-PDC) induced cell-surface expression of EAAT4 in a receptor-independent manner. The activity-dependent trafficking of this transporter which also exhibits properties of a glutamate-gated chloride channel may play functional roles not only in neuronal excitability, but in glioma cell biology as well.
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PMID:The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms. 1081 1

The Chamorro people of Guam have been afflicted with a complex of neurodegenerative diseases (now known as ALS-PDC) with similarities to ALS, AD, and PD at a far higher rate than other populations throughout the world. Chamorro consumption of flying foxes may have generated sufficiently high cumulative doses of plant neurotoxins to result in ALS-PDC neuropathologies, since the flying foxes forage on neurotoxic cycad seeds.
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PMID:Cycad neurotoxins, consumption of flying foxes, and ALS-PDC disease in Guam. 2635 84

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder of Chamorro residents of Guam and the Mariana Islands, characterized by abundant neuron loss and tau neurofibrillary pathology similar to that observed in Alzheimer's disease (AD). A variety of neurodegenerative diseases with tau pathology including ALS/PDC also have alpha-synuclein positive pathology, primarily in the amygdala. We further characterized the tau and alpha-synuclein pathology in the amygdala of a large series of 30 Chamorros using immunohistochemical and biochemical techniques. Tau pathology was readily detected in both affected and unaffected Chamorros. In contrast, alpha-synuclein pathology was detected in 37% of patients with PDC but not detected in Chamorros without PDC or AD. The alpha-synuclein aggregates often co-localized within neurons harboring neurofibrillary tangles suggesting a possible interaction between the two proteins. Tau and alpha-synuclein pathology within the amygdala is biochemically similar to that observed in AD and synucleinopathies, respectively. Thus, the amygdala may be selectively vulnerable to developing both tau and alpha-synuclein pathology or tau pathology may predispose it to synuclein aggregation. Furthermore, in PDC, tau and alpha-synuclein pathology occurs independent of beta-amyloid deposition in amygdala thereby implicating the aggregation of these molecules in the severe neurodegeneration frequently observed in this location.
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PMID:Tau and alpha-synuclein pathology in amygdala of Parkinsonism-dementia complex patients of Guam. 1200 Jul 24

Hohara and Kozagawa in the Kii peninsula of Japan are reported to be high-incidence foci of amyotrophic lateral sclerosis (Kii ALS) and parkinsonism-dementia complex (Kii PDC). During the period between 1996 and 1999, three Kii ALS patients and 19 Kii PDC patients were confirmed neurologically in Hohara among which, one Kii ALS patient and two Kii PDC patients were examined neuropathologically. The ratio of positive family history where ALS or PDC occurred within the fourth degree of the relatives was 33.3% in the patients with Kii ALS, 78.9% in those with Kii PDC, and 72.7% in total. The ages of onset were between 57 years and 63 years (mean age: 60.0 years) in the patients with Kii ALS and between 53 years and 74 years (mean age: 66.5 years) in those with Kii PDC. All of the Kii ALS patients were female, and the male to female ratio of the Kii PDC patients was 1:1.7. The clinical features of Kii ALS were basically similar to those of classical ALS. The core clinical features of Kii PDC consisted of dementia and parkinsonism, frequently accompanied by motor neuron symptoms. The cardinal neuropathological features of Kii ALS/PDC included many neurofibrillary tangles (NFTs) associated with loss of nerve cells in the cerebral cortex and the brain stem, as well as morphological alterations diagnostic of ALS. Ultrastructurally, NFTs consisted of paired helical filaments. When we compared the clinical features of these Kii ALS patients with those that had been surveyed in 1969, the male to female ratio changed from male dominance to female dominance and the mean age of the onset of the disease was delayed by approximately 10 years. The most frequent initial symptom had been weakness of the lower limbs in the survey in 1969 and was bulbar palsy in this study. As to Kii PDC, this is the first report of the clinical features of many cases.
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PMID:[Neurological and neuropathological studies of amyotrophic lateral sclerosis/parkinsonism-dementia complex in the Kii Peninsula of Japan]. 1208 Jun 7

Intracytoplasmic filamentous tau inclusions are neuropathological hallmarks of amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam and the defining lesions of other neurodegenerative disorders known as tauopathies. Here we review current insights into the cell and molecular neuropathology of ALS/PDC, a common tauopathy in the Chamorro population on Guam. We also summarize recent advances in understanding this disorder through studies of transgenic (Tg) mouse models of this tauopathy. Briefly, overexpression of human tau isoforms in the central nervous system of Tg mice resulted in a neurodegenerative tauopathy with a phenotype similar to ALS/PDC. Specifically, argyrophilic, congophilic, and tau immunoreactive inclusions accumulated with age in cortical and brainstem neurons of these mice, but they were most abundant in spinal cord neurons, and the inclusions contained 10- to 20-nm tau-positive straight filaments. There also was extensive gliosis in spinal cord associated with axonal degeneration in the ventral roots, while remaining axons in spinal nerves showed a loss of microtubules and reduced fast axonal transport. With advancing age, these Tg mice showed increasing motor weakness, and this was accompanied by a progressive increase in the phosphorylation and insolubility of brain and spinal cord tau proteins. Thus, tau Tg mice recapitulate key phenotypic features of ALS/PDC neuropathology in an ethnic minority on Guam, and these animal models provide new opportunities to discover novel therapies for this and related tauopathies.
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PMID:Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam. 1209 78

Consumption of cycad seed products (Cycas circinalis) is one of the strongest epidemiological links to the Guamian neurological disorder amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), however, the putative toxin which causes neurodegeneration has never been identified definitively. To reexamine this issue, 6-7-mo-old, male CD-1 mice were assessed for motor and cognitive behaviours during and following feeding with pellets made from washed cycad flour. Cycad-fed animals showed early evidence of progressive motor and cognitive dysfunctions. Neurodegeneration measured using TUNEL and caspase-3 labeling was found in neocortex, various hippocampal fields, substantia nigra, olfactory bulb, and spinal cord. In vitro studies using rat neocortex have identified toxic compounds in washed cycad flour that induce depolarizing field potentials and lead to release of lactate dehydrogenase (LDH), both blocked by AP5. High-performance liquid chromatography (HPLC)/mass spectrometry of cycad flour samples failed to show appreciable amounts of other known cycad toxins, cycasin, MAM, or BMAA; only trace amounts of BOAA were present. Isolation procedures employing these techniques identified the most toxic component as beta-sitosterol beta-D-glucoside (BSSG). The present data suggest that a neurotoxin, or a toxic metabolite, not previously identified in cycad, is able to gain access to central nervous system (CNS) resulting in neurodegeneration of specific neural populations and in motor and cognitive dysfunctions. These data are consistent with a number of major features of ALS-PDC in humans.
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PMID:Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour. 1209 62

The factors responsible for ALS-parkinsonism dementia complex (ALS-PDC), the unique neurological disorder of Guam, remain unresolved, but identification of causal factors could lead to clues for related neurodegenerative disorders elsewhere. Earlier studies focused on the consumption and toxicity of the seed of Cycas circinalis, a traditional staple of the indigenous diet, but found no convincing evidence for toxin-linked neurodegeneration. We have reassessed the issue in a series of in vitro bioassays designed to isolate non-water soluble compounds from washed cycad flour and have identified three sterol beta-d-glucosides as potential neurotoxins. These compounds give depolarizing field potentials in cortical slices, induce alterations in the activity of specific protein kinases, and cause release of glutamate. They are also highly toxic, leading to release of lactate dehydrogenase (LDH). Theaglycone form, however, is non-toxic. NMDA receptor antagonists block the actions of the sterol glucosides, but do not compete for binding to the NMDA receptor. The most probable mechanism leading to cell death may involve glutamate neuro/excitotoxicity. Mice fed cycad seed flour containing the isolated sterol glucosides show behavioral and neuropathological outcomes, including increased TdT-mediated biotin-dUTP nick-end labelling (TUNEL) positivity in various CNS regions. Astrocytes in culture showed increased caspase-3 labeling after exposure to sterol glucosides. The present results support the hypothesis that cycad consumption may be an important factor in the etiology of ALS-PDC and further suggest that some sterol glucosides may be involved in other neurodegenerative disorders.
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PMID:Isolation of various forms of sterol beta-D-glucoside from the seed of Cycas circinalis: neurotoxicity and implications for ALS-parkinsonism dementia complex. 1215 76


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