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)

Exposure to cycad seed kernel is an etiologic factor for the western Pacific amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC). Traditionally processed cycad flours (n = 17) obtained from Chamorro residents of Guam and the adjacent island of Rota at risk for neurodegenerative disease were extracted and analyzed by high-performance liquid chromatography for content of beta-N-methylamino-L-alanine (BMAA) and methyl-azoxymethanol beta-D-glucoside (cycasin). Cycasin (detection limit: picomole) was present in concentrations of 0.004 to 75.93 micrograms/g (mean, 12.45 +/- 5.0 micrograms/g), and levels of BMAA (detection limit: subpicomole) ranged from 0.00 to 18.39 micrograms/g (mean, 5.44 +/- 1.56 micrograms/g). On average, cycasin content was approximately 10 times higher than that of BMAA. The largest concentrations of cycasin were found in samples from villages with a high reported prevalence of ALS/PDC. Ingestion of cycad-derived food would result in estimated human exposure to milligram amounts of cycasin per day. The cytotoxic properties of cycasin merit consideration in relation to the etiology of western Pacific ALS/PDC.
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PMID:Content of the neurotoxins cycasin (methylazoxymethanol beta-D-glucoside) and BMAA (beta-N-methylamino-L-alanine) in cycad flour prepared by Guam Chamorros. 162 Mar 43

The medicinal and food use of seed from the cycad plant (Cycas spp.), which contains the neurotoxin cycasin, is a proposed etiological factor for amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC), a prototypical neurodegenerative disease found in the western Pacific. Cycasin, the beta-D-glucoside of methylazoxymethanol might enter neurons and other cells via a glucose transporter. Since the intestinal brush-border Na+/glucose cotransporter plays a major role in the absorption of monosaccharides, the following studies were conducted to determine if cycasin, the beta-D-glucoside of methylazoxymethanol, is a substrate for the transporter. We measured the ability of cycasin to (i) inhibit Na+/glucose uptake into rabbit intestinal brush-border membrane vesicles, and (ii) to generate current by the cloned Na+/glucose cotransporter (SGLT1) expressed in Xenopus laevis oocytes. The results show that cycasin inhibits Na(+)-dependent sugar transport in the vesicles, and cycasin generates phlorizin-sensitive currents in oocytes. We conclude that cycasin is a substrate for the intestinal brush-border Na+/glucose cotransporter, albeit with a lower affinity than D-glucose. This suggests that cycasin may be absorbed from the gut lumen by the cotransporter, and as a result either cycasin or the aglycone is presented to the blood-brain barrier for uptake into the brain.
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PMID:Transport of cycasin by the intestinal Na+/glucose cotransporter. 803 85

Although cycasin (methylazoxymethanol beta-D-glucoside) is proposed to be a significant etiological factor for the prototypical neurodegenerative disorder Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex, the mechanism underlying transport of cycasin across the blood-brain barrier (BBB) is unknown. We examined cycasin transport in cultured bovine brain endothelial cells, a major element of the BBB. Cycasin was taken up into endothelial cells in a dose-dependent manner with maximal uptake observed at a concentration of 10 microM. Cycasin uptake was significantly inhibited by alpha-methyl-D-glucoside, a specific analogue for the Na+-dependent glucose transporter (SGLT), by the SGLT inhibitor phlorizin, by replacement of extracellular NaCl with LiCl, and by dinitrophenol (DNP), an inhibitor of energy metabolism. In addition, cycasin produced inward currents in a whole-cell voltage clamp configuration. Peak currents were observed at 10 microM with a trend toward reduction at higher concentrations, and currents were clearly blocked by alpha-methyl-D-glucoside, phlorizin, and DNP. In addition, cycasin never evoked currents in Na+-free extracellular solution. These results suggest that cycasin is selectively transported across brain endothelial cells, possibly across the BBB by a Na+/energy-dependent glucose transporter.
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PMID:Na+-dependent and phlorizin-inhibitable transport of glucose and cycasin in brain endothelial cells. 945 73

As in Alzheimer's disease, brains of Guam Chamorros with amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) contain intraneuronal-paired helical filaments composed of accumulated phosphorylated tau protein. Tau mRNA expression in rat neuronal cultures-normally modulated by glutamate-increases after treatment with the aglycone of cycasin, a cycad-derived toxin whose concentration in Chamorro food varies with disease incidence. Elevated Tau gene expression in vitro is coincident with increased cycasin-related DNA adducts and reduced DNA repair. Cycasin and endogenous glutamate may together promote the accumulation of tau protein and neuronal degeneration in Western Pacific ALS/PDC.
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PMID:The Guam cycad toxin methylazoxymethanol damages neuronal DNA and modulates tau mRNA expression and excitotoxicity. 991