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

The cyanobacterial neurotoxin, beta-N-methylamino-l-alanine (BMAA), has been suggested as an important environmental factor for neurodegenerative disease such as amyotrophic lateral sclerosis- Parkinsonism dementia complex (ALS/PDC) in Guam. BMAA was detected within the majority of cyanobacterial isolates surveyed in both free and symbiotic cyanobacteria, living in freshwater as well as marine environments. In this study, we report two methods using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) each coupled with a different type of hydrophilic interaction liquid chromatography (HILIC) column to detect BMAA. A third method using AQC-derivatized BMAA was also used for comparison. Axenic cultures of Microcystis aeruginosa and Nostoc sp. isolated from Chinese freshwater were analyzed for both free and protein-bound BMAA at the exponential growth stage. Cultures of two strains of M. aeruginosa collected at four growth stages were also analyzed for the presence of BMAA. BMAA was detected in the Nostoc sp. at very low concentrations (<0.07pmoles on column) only when precolumn AQC derivatization was used. No BMAA was detected in the Chinese derived axenic cultures of Microcystis; detection limits for the LC-ESI-MS and LC-ESI-MS/MS without precolumn derivatization were 10ng and 2pg BMAA on column, respectively. We suggest that cyanobacteria grown under some culture conditions may be relatively free of BMAA.
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PMID:Detection of the neurotoxin BMAA within cyanobacteria isolated from freshwater in China. 1982 66

Excitement about neurogenetics in the last two decades has diverted attention from environmental causes of sporadic ALS. Fifty years ago endemic foci of ALS with a frequency one hundred times that in the rest of the world attracted attention since they offered the possibility of finding the cause for non-endemic ALS throughout the world. Research on Guam suggested that ALS, Parkinson's disease and dementia (the ALS/PDC complex) was due to a neurotoxic non-protein amino acid, beta-methylamino-L-alanine (BMAA), in the seeds of the cycad Cycas micronesica. Recent discoveries that found that BMAA is produced by symbiotic cyanobacteria within specialized roots of the cycads; that the concentration of protein-bound BMAA is up to a hundred-fold greater than free BMAA in the seeds and flour; that various animals forage on the seeds (flying foxes, pigs, deer), leading to biomagnification up the food chain in Guam; and that protein-bound BMAA occurs in the brains of Guamanians dying of ALS/PDC (average concentration 627 microg/g, 5 mM) but not in control brains have rekindled interest in BMAA as a possible trigger for Guamanian ALS/PDC. Perhaps most intriguing is the finding that BMAA is present in brain tissues of North American patients who had died of Alzheimer's disease (average concentration 95 microg/g, 0.8mM); this suggests a possible etiological role for BMAA in non-Guamanian neurodegenerative diseases. Cyanobacteria are ubiquitous throughout the world, so it is possible that all humans are exposed to low amounts of cyanobacterial BMAA, that protein-bound BMAA in human brains is a reservoir for chronic neurotoxicity, and that cyanobacterial BMAA is a major cause of progressive neurodegenerative diseases including ALS worldwide. Though Montine et al., using different HPLC method and assay techniques from those used by Cox and colleagues, were unable to reproduce the findings of Murch et al., Mash and colleagues using the original techniques of Murch et al. have recently confirmed the presence of protein-bound BMAA in the brains of North American patients dying with ALS and Alzheimer's disease (concentrations >100 microg/g) but not in the brains of non-neurological controls or Huntington's disease. We hypothesize that individuals who develop neurodegenerations may have a genetic susceptibility because of inability to prevent BMAA accumulation in brain proteins and that the particular pattern of neurodegeneration that develops depends on the polygenic background of the individual.
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PMID:Beyond Guam: the cyanobacteria/BMAA hypothesis of the cause of ALS and other neurodegenerative diseases. 1992 26

Because of the similarity of ALS/PDC symptoms to those of the paralytic disease lathyrism, cycad seeds from Guam were analyzed for the presence of the non-protein amino acid b-ODAP, which is known to cause lathyrism. Although b-ODAP was not detected, a novel non-protein amino acid, now known as BMAA, was isolated. Primates are more sensitive to BMAA than rodents. It is possible that BMAA when ingested at a low concentration over a long period might be responsible for ALS/PDC. Some non-protein amino acids, including domoic acid and indospicine, are known to be biomagnified. Other non-protein amino acids including azetidine-2-carboxylic acid, canavanine, and selenium containing analogues of cystine and methionine have been shown to be misincorporated into proteins. Perhaps BMAA will not be the only non-protein amino acid that will be found in the brain tissues of those who died of a neurological disease.
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PMID:The discovery of BMAA, and examples of biomagnification and protein incorporation involving other non-protein amino acids. 1992 27

Beta-methyl-amino-L-alanine, (BMAA), is found in multiple components of the traditional Chamorro diet of Guam and this confounds epidemiological analysis based on a single dietary item. However, using hair as a non-invasive measure of BMAA exposure may help determine risks for developing motor neuron disease. BMAA found in brain tissues of patients with ALS/PDC and not generally in controls suggests that BMAA crosses the blood-brain barrier in patients with disease and is associated with neurodegenerative disease. An examination of frozen versus fixed autopsy tissue from ALS/PDC patients suggests that earlier studies of BMAA in ALS/PDC patients based on fixed tissues may have underestimated the concentration of BMAA in brain tissues. We suggest that the Chamorro people are exposed to chronically low levels of BMAA in the diet and that further research is needed to understand chronic BMAA toxicity.
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PMID:Multiple neurotoxic items in the Chamorro diet link BMAA with ALS/PDC. 1992 29

The traditional diet of the Chamorro people of Guam has high concentrations of the neurotoxin BMAA, beta-methyl-amino-L-alanine, in cycad tortillas and from animals that feed on cycad seeds. We measured BMAA concentration in washed cycad flour and compared different extraction methods used by previous researchers in order to determine how much BMAA may have been unaccounted for in prior research. Samples were analyzed with AQC precolumn derivatization using HPLC-FD detection and verified with UPLC-UV, UPLC-MS, and triple quadrupole LC/MS/MS. Although previous workers had studied only the free amino acid component of BMAA in washed cycad flour, we detected significant levels of protein-associated BMAA in washed cycad flour. These data support a link between ALS/PDC and exposure to BMAA.
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PMID:Previous studies underestimate BMAA concentrations in cycad flour. 1992 30

Abstract The toxin ss-N-methylamino-L-alanine (BMAA) was proposed to contribute to the ALS/Parkinsonism-dementia complex of Guam (ALS/PDC) based on its presence in cycad seeds, which constituted a dietary item in afflicted populations, and its ability to induce a similar disease phenotype in primates. Although the role of BMAA in human neurodegenerative disease is still highly debated, it appears to injure cultured neurons via mechanisms involving overactivation of neuroexcitatory glutamate receptors. However, BMAA lacks the side-chain acidic group of glutamate and other excitatory amino acids, and in its place has an amino group. In past studies we found that toxic and excitatory effects of BMAA on cultured neurons were dependent upon the presence of bicarbonate in the medium, and suggested that formation of a carbamate adduct of the side-chain amino group might produce structures capable of activating glutamate receptors. Also, while BMAA is a weal agonist at NMDA-type glutamate receptors, we found low levels of BMAA to selectively damage vulnerable sub-populations of neurons, including motor neurons, via activation of AMPA/kainate receptors. Recent reports that BMAA is produced by cyanobacteria in diverse ecosystems and is present in brain and spinal cord tissues from sporadic ALS and Alzheimer's patients as well as brains of ALS/PDC patients provide strong motivation for further investigations of its toxic mechanisms and contributions to human disease.
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PMID:BMAA--an unusual cyanobacterial neurotoxin. 1992 32

Beta-N-methylamino-L-alanine (BMAA) is a non-protein amino acid, thought to be inflicting neurodegenerative diseases related to ALS/PDC in human beings. Due to conflicting data concerning the presence of BMAA in various biological matrixes, we present a robust and sensitive method for high confidence identification of BMAA after derivatization by 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC). The efficient sample pretreatment in combination with LC-MS/MS SRM enables chromatographic separation of BMAA from the isomer 2,3-diaminobutyric acid (DAB). The method is applicable for selective BMAA/DAB detection in various biological samples ranging from a prokaryotic cyanobacterium to eukaryotic fish.
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PMID:Analytical protocol for identification of BMAA and DAB in biological samples. 2002 92

In the 1960's, ALS was highly prevalent in the southern part of the Kii Peninsula, especially in the Koza, Kozagawa, and Kushimoto area (K area). Thereafter, the incidence of ALS was considered to have gradually decreased, and the disease almost disappeared in the 1980's. However, new patients have been continuously identified in this area, and indicating the importance of studying the changes in the incidences of ALS. This study investigated the characteristic clinical features and incidence of ALS in K area during the following periods: period I: between 1967 and 1971, period II: between 1989 and 1999, and period III: between 2000 and 2008. Data on all patients with motor neuron disease were collected for each year within these periods from medical doctors and medical staff of the regional public health center and municipal office. Neurologists on our research team examined and assessed each of these patients on the basis of the El Escorial criteria. Probable and definite ALS patients diagnosed by neurologists using the El Escorial criteria in K area during the research periods were collected. The crude incidence rate of ALS in K area were similar in period I, i.e. 6.0/100,000, and in period III, i.e., 5.7/100,000. The age-, and sex-adjusted incidence (considering the 2000 census) in women in K area during period III, especially in Kozagawa district, was higher than that in periods I and II. The adjusted incidence rate in Kozagawa district was 8.8/100,000, and was higher than that in other areas of the world. The clinical features of patients in this area were quite similar to those of patients with classical ALS. Five patients from 3 families with a family history of ALS and 2 patients without a family history presented with the clinical features of ALS and PDC during these research periods. The mean age at onset for period III was higher than that in period I (p < 0.01). The frequency of ALS patients with upper-extremity onset in period III was lower than that in period I (p = 0.05), whereas the frequency of patients with bulbar-onset has recently increased. Conclusion The result of present study indicate that the recent incidence of ALS in K area is high, the age of onset has recently become higher and the number of bulbar-onset patients has increased. All the abovementioned findings could be attributed to an increase in the senility rate in the population. Between 2000 and 2008, the age-adjusted incidence in ALS for women in K area, especially in the Kozagawa district, was high, indicating an increase in that the incidence of ALS among women in this area after 2000. The factors responsible for the high incidence of ALS in this area remain to be clarified.
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PMID:[Changes in the incidence and clinical features of ALS in the Koza, Kozagawa, and Kushimoto area of the Kii Peninsula--from the 1960s to the 2000s (follow-up study)]. 2011 94

Amyotrophic lateral sclerosis-Parkinson dementia complex (ALS-PDC) is a neurodegenerative disease with ALS, parkinsonism, and Alzheimer's symptoms that is prevalent in the Guam population. beta-N-Methylamino alanine (BMAA) has been proposed as the toxic agent damaging several neuronal types in ALS-PDC, including substantia nigra pars compacta dopaminergic (SNpc DAergic) neurons. BMAA is a mixed glutamate receptor agonist, but the specific pathways activated in DAergic neurons are not yet known. We combined electrophysiology, microfluorometry, and confocal microscopy analysis to monitor membrane potential/current, cytosolic calcium concentration ([Ca(2+)](i)) changes, cytochrome-c (cyt-c) immunoreactivity, and reactive oxygen species (ROS) production induced by BMAA. Rapid toxin applications caused reversible membrane depolarization/inward current and increase of firing rate and [Ca(2+)](i) in DAergic neurons. The inward current (I(BMAA)) was mainly mediated by activation of metabotropic glutamate receptor 1 (mGluR1), coupled to transient receptor potential (TRP) channels, and to a lesser extent, AMPA receptors. Indeed, mGluR1 (CPCCOEt) and TRP channels (SKF 96365; Ruthenium Red) antagonists reduced I(BMAA), and a small component of I(BMAA) was reduced by the AMPA receptor antagonist CNQX. Calcium accumulation was mediated by mGluR1 but not by AMPA receptors. Application of a low concentration of NMDA potentiated the BMAA-mediated calcium increase. Prolonged exposure to BMAA caused significant modifications of membrane properties, calcium overload, cell shrinkage, massive cyt-c release into the cytosol and ROS production. In SNpc GABAergic neurons, BMAA activated only AMPA receptors. Our study identifies the mGluR1-activated mechanism induced by BMAA that may cause the neuronal degeneration and parkinsonian symptoms seen in ALS-PDC. Moreover, environmental exposure to BMAA might possibly also contribute to idiopathic PD.
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PMID:Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative beta-N-Methylamino-L-alanine on substantia nigra pars compacta DAergic neurons. 2039 40

Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, recent attention has focused on the early, non-motor symptoms, which include but are not limited to sleep disorders such as excessive daytime sleepiness (EDS) and REM behavioral disorder (RBD). However, few animal models have been able to replicate both the motor and non-motor symptoms of PD. Here, we present a progressive rat model of parkinsonism that displays disturbances in sleep/wake patterns. Epidemiological studies elucidated a link between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant Cycas micronesica (cycad). Our study examined the effects of prolonged cycad consumption on sleep/wake activity in male, Sprague-Dawley rats. Cycad-fed rats exhibited an increase in length and/or number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep at the expense of wakefulness during the active period when compared to control rats. This hypersomnolent behavior suggests an inability to maintain arousal. In addition, cycad-fed rats had significantly fewer orexin cells in the hypothalamus. Our results reveal a novel rodent model of parkinsonism that includes an EDS-like syndrome that may be associated with a dysregulation of orexin neurons. Further characterization of this early, non-motor symptom, may provide potential therapeutic interventions in the treatment of PD.
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PMID:Sleep alterations in an environmental neurotoxin-induced model of parkinsonism. 2071 46


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