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 cerebrospinal fluid (CSF) is a specific ultrafiltrate of plasma, which surrounds the brain and spinal cord. The study of its proteins and their alteration may yield useful information on several neurological diseases. By using various electrophoretic separation techniques, several CSF proteins have been identified derived from plasma or from brain. Different one-dimensional methods, such as agarose gel electrophoresis and isoelectric focusing, are of similar value in identifying the non-specific oligoclonal bands, which are mainly helpful in the diagnosis of multiple sclerosis and other inflammatory diseases. Isoelectric focusing has a greater resolution than other one-dimensional methods, and it yields additional data about disease-associated proteins occurring in Alzheimer's disease, Huntington's chorea and amyotrophic lateral sclerosis. Silver-stained two-dimensional gels provide more information about the complex protein composition of CSF, particularly about proteins produced in the brain, such as apolipoprotein E and neuron-specific enolase. For the detection of oligoclonal antibodies, the investigation of protein changes revealed by Parkinson's disease, schizophrenia and Creutzfeldt-Jakob disease, and the analysis of CSF immune complexes, two-dimensional electrophoresis has a greater sensitivity.
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PMID:Analysis of cerebrospinal fluid proteins by electrophoresis. 193 90

Apolipoprotein E allele 4 (apo E epsilon 4) is known to be in genetic disequilibrium with Alzheimer's disease and is associated with an earlier age at onset of dementia. Whether apo E epsilon 4 is a specific risk factor for Alzheimer's disease or is a more general susceptibility factor that shifts the age at onset of neurodegenerative diseases to earlier ages is unknown. To test these possibilities, we determined the apolipoprotein E genotypes of subjects with familial or sporadic amyotrophic lateral sclerosis (ALS). ApoE allele frequencies of the apoE gene of the ALS subjects (n = 170, epsilon 2 = 0.071, epsilon 3 = 0.771, epsilon 4 = 0.159) were found to be comparable to the allele frequencies of the general population. Furthermore, no significant association was observed between the age at onset or the duration of ALS and the inheritance of apoE epsilon 4: subjects with at least one copy of epsilon 4 (sporadic ALS: n = 15, onset at 57.7 +/- 13.9 years; familial ALS: n = 23, onset at 53.6 +/- 9.5 years, duration [n = 14] of 2.6 +/- 1.6 years) had comparable ages at onset and durations to subjects without epsilon 4 (sporadic ALS: n = 28, onset at 53.1 +/- 17.0 years; familial ALS: n = 56, onset at 50.8 +/- 12.1 years, duration [n = 30] of 1.9 +/- 0.8 years). The lack of association of apoE epsilon 4 with the age at onset and the duration of ALS suggests that apoE epsilon 4 does not have a global effect on the pathogenesis of other neurodegenerative diseases.
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PMID:Apolipoprotein E epsilon 4 allele is not associated with earlier age at onset in amyotrophic lateral sclerosis. 766 34

The distribution of apolipoprotein E (ApoE) was studied in the brain tissue of cases of the amyotrophic lateral sclerosis-parkinsonism-dementia complex of Guam, locally known as lytico bodig disease (LB), and compared with cases of Alzheimer's disease (AD) and normal brain tissue. In both LB and AD, strong ApoE immunostaining was observed in association with pathological lesions. In LB, these were mainly extracellular neurofibrillary tangles (eNFTs) which were intensely immuno-positive for ApoE. Occasional diffuse beta-amyloid protein (beta AP) deposits appear in this disorder and they were moderately immunopositive. In AD, senile plaques and diffuse beta AP deposits were intensely immunopositive, while eNFTs were only moderately immunopositive. The reason for the strong association of ApoE with the pathological entities in LB and AD is unknown, but may be related to a scavenger function which does not involve lipid metabolism. In both LB and AD, subpial and layer I diffuse deposits were ApoE negative but beta AP positive. Intracellular NFTs were mostly ApoE negative. A few showed weak positive staining. These data suggest that ApoE appears in LB and AD pathological lesions only after they are well established. In all controls, as well as all LB and AD cases, strong ApoE immunoreactivity was observed in unidentifiable structures in capillaries. Weak staining in a few neurons and very weak staining of an occasional astrocyte was observed. The source of ApoE which is deposited on extracellular pathological structures in LB and AD is unknown.
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PMID:Distinct distribution of apolipoprotein E and beta-amyloid immunoreactivity in the hippocampus of Parkinson dementia complex of Guam. 889 Oct 70

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disorder of unknown etiology. Recently, in Alzheimer's disease (AD) apolipoprotein E (APOE) alleles have been shown to play an important role in disease phenotype. To determine whether APOE have a similar influence in other neurodegenerative disorders, we studied APOE genotypes in 130 sporadic ALS patients, compared with controls. We also analyzed APOE genotypes regarding ALS clinical criteria. The frequency of APOE genotypes was not different between ALS and controls. However, subjects with the APOE2/E3 genotype showed a significantly longer duration of the disease: 51 months vs. 28.5 for APOE3/E3 and 27.5 for APOE3/E4 (p = 0.001 and p = 0.02, respectively). There was a significantly higher proportion of bulbar ALS patients in the APOE3/E4 group (72% of the cases), whereas 90% of patients in the APOE2/E3 group showed limb onset (p = 0.01). In the bulbar group, patients with APOE4 showed earlier onset of the disease: 60 vs. 66 years (mean age, p = 0.05). These results are consistent with a protective role of APOE2 and a deleterious role of APOE4 in ALS as already found for AD. This parallel supports the idea of a general role of APOE in neuronal degeneration or regeneration rather than a specific role in ALS or AD etiopathogenesis.
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PMID:Apolipoprotein E genotyping in sporadic amyotrophic lateral sclerosis: evidence for a major influence on the clinical presentation and prognosis. 889 55

Advanced glycation end products (AGEs) have been implicated in the chronic complications of diabetes mellitus and have been reported to play an important role in the pathogenesis of Alzheimer's disease. In this study, we examined the immunohistochemical localization of AGEs, amyloid beta protein (A beta), apolipoprotein E (ApoE), and tau protein in senile plaques, neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy (CAA) in Alzheimer's disease and other neurodegenerative diseases (progressive supranuclear palsy, Pick's disease, and Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex). In most senile plaques (including diffuse plaques) and CAA from Alzheimer's brains, AGE and ApoE were observed together. However, approximately 5% of plaques were AGE positive but A beta negative, and the vessels without CAA often showed AGE immunoreactivity. In Alzheimer's disease, AGEs were mainly present in intracellular NFTs, whereas ApoE was mainly present in extracellular NFTs. Pick's bodies in Pick's disease and granulovacuolar degeneration in various neurodegenerative diseases were also AGE positive. In non-Alzheimer neurodegenerative diseases, senile plaques and NFTs showed similar findings to those in Alzheimer's disease. These results suggest that AGE may contribute to eventual neuronal dysfunction and death as an important factor in the progression of various neurodegenerative diseases, including Alzheimer's disease.
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PMID:Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. 977 46

Amyotrophic lateral sclerosis (ALS) is a neuro-degenerative disorder with both sporadic and familial forms. Approximately 20% of autosomal dominant ALS is caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene. The causes of the remaining forms of ALS are unknown. The apolipoprotein E (APOE) gene is a known genetic risk factor for Alzheimer disease (AD), another neuro-degenerative disease. The APOE-4 allele increases risk and decreases age at onset in AD. Studies examining ALS and APOE have failed to show a significant effect of APOE on overall risk in ALS. Studies examining the effect of APOE-4 on site of onset in ALS (bulbar or limb) have been contradictory, with some studies showing an APOE association with bulbar onset and others showing no effect. Sample size was limited in these previous reports, particularly with respect to the number of bulbar onset cases (n = 33, 34 and 53). The present study examines a large collaborative data set of ALS patients (n = 363; 95 with bulbar onset) and age-matched neurologically normal controls. The results for these data showed no significant differences in the percentage of subjects with the APOE-4/4 and APOE-4/X genotypes (X = APOE-2 or APOE-3) when comparing cases and controls in both the overall data set or in the data set stratified by site of onset. Similarly, logistic regression analysis in the overall and stratified data set while controlling for sex showed no increase or decrease in risk of ALS associated with the APOE-4 allele. In addition, there were no significant differences in age at onset between patients with APOE-X/X, and APOE-4/4 or APOE-4/X genotypes, overall or stratified by site of onset. We conclude based on these data that the APOE gene is not a major genetic risk factor for site of onset in ALS.
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PMID:Lack of association between apolipoprotein E genotype and sporadic amyotrophic lateral sclerosis. 1073 25

Inheritance of the apolipoprotein E (apoE) epsilon4 allele increases the risk for Alzheimer's disease and may also influence the pathogenesis of other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). The influence of apoE genotype on disease susceptibility must ultimately be explained by the fact that apoE proteins differ in only two amino acids: apoE2 has two cysteine residues, apoE3 has one cysteine residue, and apoE4 has none. We previously reported increased protein modification by the lipid peroxidation product 4-hydroxynonenal (HNE), which covalently binds to proteins on cysteine residues, in human ALS lumbar spinal cord. We now report increased levels of HNE-modified apoE in lumbar spinal cord samples from mice expressing an ALS-linked mutation in Cu/Zn-superoxide dismutase relative to controls. Studies of interactions of pure apoE proteins with HNE showed that the isoforms differ in the amount of HNE they can bind, with the order E2 > E3 > E4. This correlated with the differential ability of apoE isoforms to protect against apoptosis induced by HNE in cultures of mouse spinal cord motor neurons and by the amyloid beta-peptide in cultures of rat hippocampal neurons. These data suggest that apoE plays a major role in detoxifying HNE, and the differential neuroprotective effect of its isoforms may help explain the relationship between apoE genotype and the susceptibility to neurodegenerative diseases.
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PMID:A mechanism for the neuroprotective effect of apolipoprotein E: isoform-specific modification by the lipid peroxidation product 4-hydroxynonenal. 1073 98

Molecular mechanisms that alter the incidence and rate of neuromuscular disease progression are, in many cases, only partially understood. Several recent studies have asked whether apolipoprotein E (apoE for the protein, APOE for the gene) influences these aspects of specific neuromuscular disorders, as it does in central nervous system disorders such as Alzheimer disease. Although these studies are open to methodological criticism, several interesting trends have emerged. First, the APOE4 allele seems to be associated with an increased risk for developing certain neuromuscular diseases, including diabetic neuropathy and human immunodeficiency viral neuropathy. Second, this allele appears to be associated with faster progression of some neuromuscular diseases, including diabetic neuropathy and possibly motor neuron disease. Third, the APOE2 allele seems to confer protection against developing certain neuromuscular diseases, including the amyotrophic lateral sclerosis (ALS)/parkinsonism/dementia complex of Guam. Finally, this allele is associated with a better prognosis in neuromuscular diseases such as motor neuron disease. The effect of various APOE alleles on neuromuscular diseases therefore parallels their influence on central nervous system diseases. Arch Neurol. 2000;57:1561-1565
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PMID:Apolipoprotein E and neuromuscular disease: a critical review of the literature. 1107 87

Gain-of-function mutations of the Cu/Zn superoxide dismutase (SOD1) gene cause dominantly inherited familial amyotrophic lateral sclerosis. The identification of differentially regulated proteins in spinal cords of paralyzed mice expressing SOD1(G93A) may contribute to understanding mechanisms of toxicity by mutant SOD1. Protein profiling showed dysregulation of Stathmin with a marked decrease of its most acidic and phosphorylated isoform, and up-regulation of heat shock proteins 25 and 27, peroxiredoxin 6, phosphatidylinositol transfer protein-alpha, apolipoprotein E, and ferritin heavy chain. Stathmin accumulated in the cytoplasm of 30% of spinal cord motor neurons with fragmented Golgi apparatus. Overexpression of Stathmin in HeLa cells was associated with collapse of microtubule networks and Golgi fragmentation. These results, together with the decrease of one Stathmin isoform, suggest a role of the protein in Golgi fragmentation. Mutant SOD1 co-precipitated and co-localized with Hsp25 in neurons and astrocytes. Mutant SOD1 may thus deprive cells of the anti-apoptotic and other protective activities of Hsp25. Astrocytes contained peroxiredoxin 6, a unique nonredundant antioxidant. The up-regulation of peroxiredoxin 6 probably constitutes a defense to oxidative stress induced by SOD1(G93A). Direct effects of SOD1(G93A) or sequential reactions triggered by the mutant may cause the protein changes.
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PMID:Dysregulation of stathmin, a microtubule-destabilizing protein, and up-regulation of Hsp25, Hsp27, and the antioxidant peroxiredoxin 6 in a mouse model of familial amyotrophic lateral sclerosis. 1550 39

An update of the endemic parkinsonism-dementia complex (PDC) frequently associated with amyotrophic lateral sclerosis (ALS) in the high prevalence ALS focus of the Kii peninsula of Japan is presented. The initial symptom was parkinsonian gait or hypobulia/amnesia, which was followed by akinesia, rigidity, occasional tremor, bradyphrenia, abulia and amnesia, and finally by akinetic mutism. In several years, most of the patients developed ALS symptoms such as muscle atrophy, bulbar palsy, and upper motor neuron signs. Magnetic resonance imaging and computed tomography of the brain showed marked atrophy of the temporal and frontal lobes and the cerebral blood flow reduction on single-photon emission computed tomography. Marked loss of nerve cells associated with abundant neurofibrillar tangles (NFTs) in the entire central nervous system, most predominantly in the brainstem and temporal lobe was characteristic. Concomitant ALS pathology involving the upper and lower motor neurons was common, and senile plaques were absent in most cases. NFTs consisted of twisted tubules on electron microscopy. Western blot of tau protein showed three bands consisting of six tau isoforms, similar to those of Alzheimer's disease. A family history of ALS/PDC was recorded in more than 70% of patients, but no abnormal mutation or polymorphism was found in the genes of SOD1, tau, and apolipoprotein E. Familial nature and continuing morbidity of Kii ALS/PDC suggest that genetic factors may be more likely in its pathogenesis.
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PMID:Atypical parkinsonism of Japan: amyotrophic lateral sclerosis-parkinsonism-dementia complex of the Kii peninsula of Japan (Muro disease): an update. 1609 99


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