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)

To evaluate reports of abnormal levels of free amino acids (AA) in patients with amyotrophic lateral sclerosis (ALS), we studied serum, cerebrospinal fluid, and urine AA in 12 patients with ALS and 12 controls matched for age, sex, and severity of disability. ALS patients had statistically significant elevations in serum levels of tyrosine, total aromatic AA, and total basic AA. ALS patients also had statistically significant elevations in cerebrospinal fluid of total basic AA, lysine, essential AA, and leucine. The severity of ALS correlated inversely with acidic AA (glutamate and aspartate) and O-phosphoserine in cerebrospinal fluid. Activity of ALS correlated directly with serum aspartate and cerebrospinal fluid alanine. We conclude that subtle abnormalities of AA levels are present in ALS and that these are not due to age, sex, or disability. The pattern of distribution of AA levels differs from that in hepatic or renal disease and suggests defective membrane transport or poor cellular utilization of basic and essential AA in the central nervous system.
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PMID:Free amino acid levels in amyotrophic lateral sclerosis. 66 70

At the present time, it seems unlikely that progressive neurodegenerative diseases, such as ALS, Parkinson's disease, and dementia of the Alzheimer type, are triggered by environmental agents with excitotoxic potential. These include excitotoxic agents that behave as glutamate agonists or disrupt energy metabolism: both types elicit permanent but self-limiting neuronal diseases with patterns of neuronal deficit that reflect selective chemical exposure (MPP+ and parkinsonism), differential susceptibility to energy dysmetabolism (NPA and dystonia), or the distribution of glutamate-receptors (domoic acid and memory loss). If environmental agents play an etiologic role in progressive neurodegenerative diseases, they are likely to target a critical, irreplaceable neuronal molecule that is required to maintain long-term neuronal integrity.
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PMID:Are human neurodegenerative disorders linked to environmental chemicals with excitotoxic properties? 132 79

We measured the levels of amino acids in biopsied skin from eight patients with amyotrophic lateral sclerosis (ALS) and seven controls. The most conspicuous changes in ALS patients were as follows. First, the contents of the acidic amino acids glutamate and aspartate were significantly decreased in ALS, and were negatively and significantly associated with the duration of illness. Second, the levels of the collagen-associated amino acids hydroxyproline, proline, glycine, alanine, and hydroxylysine were significantly decreased in ALS, and correlated inversely with the duration of illness. These results suggest that there are abnormalities of acidic amino acids and collagen-associated amino acids in the skin of patients with ALS. These changes may underlie the pathogenesis of ALS.
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PMID:Glutamate and aspartate are decreased in the skin in amyotrophic lateral sclerosis. 821 62

beta-N-Methylamino-L-alanine (BMAA) is a neurotoxic plant amino acid that has been implicated in the pathogenesis of the high incidence amyotrophic lateral sclerosis and related parkinsonism dementia of the western Pacific. Previous studies have demonstrated that BMAA is taken up into brain following intravenous or oral administration. To examine the kinetics and mechanism of brain transfer, BMAA influx across the blood-brain barrier was measured in rats using an in situ brain perfusion technique. BMAA influx was found to be saturable with a maximal transfer rate (Vmax) of 1.6 +/- 0.3 x 10(-3) mumol/s/g and a half-saturation constant (Km) of 2.9 +/- 0.7 mM based on total perfusate BMAA concentration. Uptake was sodium independent and inhibitable by excess L-leucine, but not by L-lysine, L-glutamate, or methylaminoisobutyric acid, indicative of transfer by the cerebrovascular large neutral amino acid carrier. L-BMAA competitively reduced brain influx of L-[14C]leucine, as expected for cross-inhibition. The results demonstrate that BMAA is taken up into brain by the large neutral amino acid carrier of the blood-brain barrier and suggest that uptake may be sensitive to the same factors that affect neutral amino acid transport, such as diet, metabolism, disease, and age.
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PMID:Facilitated transport of the neurotoxin, beta-N-methylamino-L-alanine, across the blood-brain barrier. 154 67

Evidence for a generalized defect in glutamate in patients with amyotrophic lateral sclerosis (ALS), associated with widespread alterations in the central nervous system level of this excitatory amino acid. We measured fasting plasma amino acid in 10 ALS patients and 10 controls matched for age and sex. ALS patients had statistically significant elevations in plasma level of aspartate, glutamate, and glycine. The plasma levels of other amino acids were not significantly different from those found in controls. No correlation between ALS severity or activity and degree of abnormality in amino acids was established.
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PMID:Plasma amino acid levels in patients with amyotrophic lateral sclerosis. 156 21

Features common to amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) are reviewed. Shared epidemiological aspects include an increasing frequency which is proportional for each disease. We draw attention to geographic non-uniform distribution which, for ALS and PD, correlates positively with latitude. Clinical and pathological overlap occurs in the same patients, and in members of the same family. A high early morning plasma cysteine/sulphate ratio possibly related to the development of proteinacious inclusions, as well as ubiquinated neuronal inclusions, characterize ALS, PD and AD. HLA-DR (the human group II major histocompatibility class) staining is marked in ALS, PD and AD and may represent autoimmunity-incited by-products of neuronal degeneration. Based upon demonstrated glutaminergic connections between the neocortex and anterior horn cells, the entorhinal cortex and the basal ganglia we hypothesize that ALS, AD and PD are phylogenetic disturbances of the neocortical cell. The postsynaptic neuron may degenerate secondarily to anterograde effects of deranged glutamate metabolism. Future therapeutic strategies should be directed to agents that decrease transmission induced by excitatory amino-acids.
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PMID:Amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease: phylogenetic disorders of the human neocortex sharing many characteristics. 157 56

Acidic excitatory amino acids have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). We now report that, in addition to selective regional reductions in endogenous aspartate and glutamate, N-acetylaspartate (NAA), and N-acetylaspartylglutamate (NAAG) are also decreased in the CNS, whereas the activity of N-acetylated-alpha-linked-amino dipeptidase (NAALADase) is increased. In cervical cord, the concentrations of aspartate and glutamate were decreased significantly in the ventral horn; NAA was decreased in the ventral horn, dorsal horn and ventral column, whereas NAAG was decreased in all regions of the cord examined, except the posterior column. NAALADase activity was increased in the ventral column. In motor cortex of ALS patients, aspartate and glutamate were decreased and NAALADase activity was increased in both gray and white matter; whereas NAAG was decreased in gray matter alone. None of these parameters was affected in the cerebral cortex of the Huntington's patients. Of the markers examined, the alterations in the levels of NAAG most closely parallel the cellular neuropathology in ALS.
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PMID:Reductions in acidic amino acids and N-acetylaspartylglutamate in amyotrophic lateral sclerosis CNS. 168 6

Measurements were taken of the activity of glutamate dehydrogenase (GDH) and the levels of transmitter amino acids in anatomically dissected regions of cervical and lumbar spinal cord in eight patients dying with amyotrophic lateral sclerosis (ALS) and in 11 neurologically normal controls. GDH activity was considerably increased in lateral and ventral white matter and in the dorsal horn of the ALS cervical spinal cord, but normal in the ventral horn and the dorsal columns. Similar, although less pronounced, GDH changes were found in the lumbar enlargement. The mean concentrations of aspartate and glutamate were reduced in all regions of ALS spinal cord investigated. Taurine concentrations were significantly increased in several subdivisions of cervical spinal cord, but normal in lumbar regions. Glycine levels were significantly reduced in lumbar ventral and dorsal horns. There was no striking change in spinal cord GABA levels in our ALS patients. It is suggested that the reduced levels of glutamate and aspartate as well as the elevated GDH activity in the spinal cord of ALS patients may reflect an overactivity of the neurons releasing these potentially excitotoxic amino acids and thus may be causally related to the spinal neuro-degenerative changes characteristic of ALS.
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PMID:Amyotrophic lateral sclerosis: glutamate dehydrogenase and transmitter amino acids in the spinal cord. 168 99

Reductions in glutamate and aspartate contents, together with increased contents of taurine, have been observed in the autopsied brains and spinal cords of patients who have died with amyotrophic lateral sclerosis (ALS). The wobbler mouse develops an inherited degeneration of motoneurons within the brainstem and spinal cord, and has been proposed as an animal model of ALS. In symptomatic wobbler mice we found brain contents of glutamate, aspartate, and taurine similar to those in unaffected littermates, while brain contents of glutamine were increased, and those of serine and alanine were decreased. Spinal cords of wobbler mice had slightly decreased contents of glutamate, aspartate and glycine compared to normal littermates. Abnormalities of amino acid contents in the nervous system of wobbler mice are dissimilar to those in ALS patients suggesting a different pathogenesis of motoneuron loss.
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PMID:The wobbler mouse: amino acid contents in brain and spinal cord. 191 46

Acute neurological injury from hypoxia-ischemia, hypoglycemia, and trauma is thought to be predominantly mediated by activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in the brain and the subsequent influx of calcium ions through receptor-operated channels. Several chronic degenerative diseases, such as Huntington's disease and the amyotrophic lateral sclerosis-Parkinsonism-dementia complex found on Guam, may share a similar pathogenesis due to a glutamate-like toxin. This laboratory recently reported that exposure to a reducing agent, such as dithiothreitol (DTT), selectively increases ionic current flow through NMDA-activated channels in several types of central neurons; conversely, oxidizing agents reverse this effect. To investigate the novel influence of redox modulation on NMDA neurotoxicity, in the present in vitro study we monitored survival of an identified central neuron, the retinal ganglion cell, approximately 24 h after a brief exposure to DTT. To determine the degree of killing specifically related to activation of the NMDA receptor, 2-amino-5-phosphonovalerate (APV, a selective NMDA antagonist) was added to sibling cultures. APV-preventable, glutamate-induced death was increased 70 +/- 9% with DTT treatment. This effect was totally blocked by the concomitant addition of an oxidizing agent, 5,5-dithiobis-2-nitrobenzoic acid (DTNB). These findings suggest that the enhanced killing following chemical reduction with DTT is mediated at the NMDA receptor site, and that the redox state of the NMDA receptor is crucial for the survival of neurons facing glutamate-related injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Redox modulation of NMDA receptor-mediated toxicity in mammalian central neurons. 197 Jan 45


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