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)

The role of transmethylation mechanisms in the etiology of amyotrophic lateral sclerosis (ALS) is hitherto unexplored. The activity of L-methionine S-adenosyltransferase (MAT), a regulatory enzyme of S-adenosylmethionine biosynthesis, was investigated in erythrocytes of 21 patients with ALS, spinal cord specimens of 7 ALS patients, and matched controls. In ALS patients the activity of MAT in erythrocytes was sex-dependent. In comparison with controls, the male group presented a 33% higher V(max) (P < 0.05) and a 41% decrease in the affinity of MAT for methionine (K(m), P < 0.05). The type of ALS onset (limb or bulbar), age, or duration of the disease did not influence erythrocyte MAT activity. In the spinal cord, the activity of MAT was homogeneously distributed through dorsal horn, ventral horn, and white matter. Comparisons between data from controls and ALS patients and analysis of sex effect showed no significant differences. The kinetic difference of erythrocyte MAT in the male group of ALS patients might be interesting to explore since it is well known that there is a male predominance of 1.5 to 2. 5:1 in ALS.
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PMID:Methionine adenosyltransferase activity in erythrocytes and spinal cord of patients with sporadic amyotrophic lateral sclerosis. 1041 48

Folate deficiency contributes to a variety of age-related neurological and psychological disorders including amyotrophic lateral sclerosis (ALS). The environmental neurotoxin arsenic has recently been linked with decreased neurofilament (NF) content in peripheral nerve. We examined herein, whether or not folate deprivation potentiated the impact of arsenic on NF dynamics. Arsenic inhibited translocation of NFs into axonal neurites in culture and increased perikaryal NF phosphoepitopes. Folate deprivation potentiated the impact of arsenic on these phenomena. Supplementation with S-adenosyl methionine (SAM) attenuated the impact of folate deprivation on arsenic neurotoxicity, consistent with the decrease in SAM following folate deprivation and the requirement for SAM-mediated methylation for arsenic bioelimination. These findings demonstrate how key nutritional deficiencies can potentiate the impact of enrivonmental neurotoxins.
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PMID:Potentiation of arsenic neurotoxicity by folate deprivation: protective role of S-adenosyl methionine. 1828 27

The full range of causative factors in Amyotrophic lateral sclerosis (ALS) remains elusive, but oxidative stress is recognized as a contributing factor. Mutations in Cu/Zn superoxide dismutase 1 (SOD-1), associated with familial ALS, promote widespread oxidative damage. Mice-expressing G93A mutant human SOD-1 mice display multiple pathological changes characteristic of ALS and are therefore useful for therapeutic development. Dietary supplementation with S-adenosyl methionine (SAM) has provided multiple neuroprotective effects in mouse models of age-related cognitive pathology. We examined herein whether SAM supplementation could affect the course of motor neuron pathology in mice-expressing mutant human SOD-1. SAM delayed disease onset by 2-3 weeks. SAM also delayed hallmarks of neurodegeneration in these mice and in ALS, including preventing loss of motor neurons, and reducing gliosis, SOD-1 aggregation, protein carbonylation, and induction of antioxidant activity. SAM did not increase survival time. These preliminary findings, using a single concentration of SAM, suggest that SAM supplementation maybe useful as part of a comprehensive therapeutic approach for ALS.
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PMID:Dietary supplementation with S-adenosyl methionine delays the onset of motor neuron pathology in a murine model of amyotrophic lateral sclerosis. 1975 9

Spontaneous protein deamidation of labile asparagines (Asn), generating abnormal l-isoaspartyl residues (IsoAsp), is associated with cell aging and enhanced by an oxidative microenvironment. The presence of isopeptide bonds impairs protein structure/function. To minimize the damage, IsoAsp can be "repaired" by the protein l-isoaspartyl/d-aspartyl O-methyltransferase (PIMT) and S-adenosylmethionine (AdoMet) is the methyl donor of this reaction. PIMT is a repair enzyme that initiates the conversion of l-isoAsp (or d-Asp) residues to l-Asp residues. Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease principally affecting motor neurons. The condition of oxidative stress reported in familial and sporadic forms of ALS prompted us to investigate Asn deamidation in ALS tissue. Erythrocytes (RBCs) were selected as a model system since they are unable to replace damaged proteins and protein methylesterification is virtually the only AdoMet-consuming reaction operating in these cells. Our data show that, in vitro assay, abnormal IsoAsp residues were significantly higher in ALS patients erythrocyte membrane proteins with an increased methyl accepting capability relative to controls (p<0.05). Moreover, we observed a reduction in AdoMet levels, while AdoHcy concentration was comparable to that detected in the control, resulting in a lower [AdoMet]/[AdoHcy] ratio. Then, the accumulation of altered aspartyl residues in ALS patients is probably related to a reduced efficiency of the S-adenosylmethionine (AdoMet)-dependent repair system causing increased protein instability at Asn sites. The increase of abnormal residues represents a new protein alteration that may be present not only in red blood cells but also in other cell types of patients suffering from ALS.
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PMID:Accumulation of altered aspartyl residues in erythrocyte membrane proteins from patients with sporadic amyotrophic lateral sclerosis. 2404 98

Stress granules (SGs) are evolutionarily conserved condensates of ribonucleoproteins that assemble in response to metabolic stresses. Because aberrant SG formation is associated with amyotrophic lateral sclerosis (ALS), understanding the connection between metabolic activity and SG composition can provide therapeutic insights into neurodegeneration. Here, we identify 17 metabolic enzymes recruited to yeast SGs in response to physiological growth stress. Furthermore, the product of one of these enzymes, AdoMet, is a regulator of SG assembly and composition. Decreases in AdoMet levels increase SG formation, while chronic elevation of AdoMet produces SG remnants lacking proteins associated with the 5' end of transcripts. Interestingly, acute elevation of AdoMet blocks SG formation in yeast and motor neurons. Treatment of ALS-derived motor neurons with AdoMet also suppresses the formation of TDP-43-positive SGs, a hallmark of ALS. Together, these results argue that AdoMet is an evolutionarily conserved regulator of SG composition and assembly with therapeutic potential in neurodegeneration.
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PMID:Conserved metabolite regulation of stress granule assembly via AdoMet. 3260