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)

Anti-lymphocyte sera against human thymus [ALS-(THY)] were absorbed serially with cultured human lymphoblasts (CHL) or thymus and residual antigen-binding activity was tested. The absorbed ALS were used to bind 125I-labeled antigens from lymphocytes labeled by the lactoperoxidase catalyzed iodination technique. Absorption of ALS(THY) with CHL led to the absorbed serum having less than 5 to 10% of its original antigen-binding activity against labeled CHL antigens while maintaining from 20 to 40% of its original activity against labeled THY. Serial absorption of ALS(THY) with THY led to an equal decrease in activity against both THY and CHI. When the immunoprecipitates from these experiments were examined on polyacrylamide gels containing SDS it was found that serial absorption of ALS(THY) with THY first removed activity against a component of m.w. similar to 48,000 leaving relatively greater activity against material of apparent high molecular wieght. In contrast, absorption of ALS-(THY) with CHL removed the antibodies against the high molecular weight material while leaving activity against the component of m.w. 48,000. When these absorbed ALS were used to induce in vitro lymphocyte proliferation, it was found that ALS(THY) absorbed with CHL, did not. The retention or loss of mitogenicity seemed to correlate with retention or loss of binding activity against the component(s) of m.w. similar to 48,000.
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PMID:Lymphocyte plasma membranes. V. Specificity and mitogenicity of absorbed anti-lymphocyte sera. 115 Oct 74

We studied skin from patients with amyotrophic lateral sclerosis (ALS) and controls by electron microscopy, and analyzed it by sodium dodecyl sulfate-poly-acrylamide gel electrophoresis (SDS-PAGE) and two-dimensional gel electrophoresis. On electron microscopy, the most conspicuous finding in ALS was a markedly increased amount of amorphous material in the ground substance, which became more marked in proportion to the duration of ALS. SDS-PAGE analysis showed that in ALS patients the staining intensity of a low-molecular weight band (approx. 12.5 kDa, band "g") became more marked with the duration of ALS. Two-dimensional gel electrophoresis revealed that band "g" consisted of a single component with a basic isoelectric point. It is thought that the substance corresponding to band "g" is a major constituent of the amorphous material.
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PMID:Amyotrophic lateral sclerosis: electrophoretic study of amorphous material of skin. 233 63

Protease nexin I (PNI) is a 43- to 50-kDa glycoprotein capable of inhibiting a number of serine proteases and belongs to the serpin superfamily. PNI is identical to glia-derived nexin, a neurite outgrowth promoter by virtue of its thrombin-inhibiting activity. Of particular relevance to neuromuscular biology and pathology, PNI was the first serpin shown to be highly localized to the neuromuscular junction and it maps to precisely the same locus as autosomal recessive amyotrophic lateral sclerosis (ALSJ) at chromosome 2q33-35. In the present report, we now show that in cultures of human skeletal muscle, PNI protein is expressed only after myoblast fusion into multinuclear myotubes and is localized in patches on their surfaces. We performed complex formation experiments with labeled thrombin, another target protease for PNI, with intact human muscle cells in culture. We detected specific SDS-stable PNI/thrombin complexes in myotube extracts only, indicating that active PNI was bound to their surfaces. We studied the gene expression of PNI mRNA using a 300-bp cDNA synthesized from the published sequence of human PNI. Confirming the protein data, upregulation of PNI appears in myotubes using Northern blot analysis. The current results reinforce the hypothesis that the regulation of the balance of serine proteases and serpins, such as PNI, is involved in muscle differentiation. They also prompt us to explore PNI abnormalities in several neuromuscular diseases, including ALSJ.
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PMID:Myoblast fusion promotes the appearance of active protease nexin I on human muscle cell surfaces. 854 75

MSA is a complex disorder, with regard to its pathology and cause as well as its clinical diagnosis and treatment. Although a number of clinical treatments may improve quality of life for these patients, given the widespread pathology present, symptomatic treatment, particularly that involving neurotransmitter replacement, is likely to remain difficult. Truly effective treatment for these patients is likely to depend on an understanding of the underlying pathogenic mechanisms and methods to halt or reverse disease progression. A firm understanding of the classification of these disorders is the first step to understanding the relevant pathogenic mechanisms. The finding of intracytoplasmic glial inclusion bodies provides a compelling piece of evidence that SND, OPCA, and SDS do, in fact, belong to one nosologic entity. These inclusions do not seem to be present in familial cases of OPCA; thus, they may provide a means to improve diagnostic specificity as well as sensitivity. With the ability to define clearly the entity of MSA, an understanding of the pathophysiology can be developed along with other degenerative neurologic diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease.
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PMID:Multiple system atrophy. 1009 84

In an attempt to identify unique disease-related autoantibodies, the serum from an ataxia and sensory neuropathy patient was used as a probe to isolate a 2.5-kd cDNA from a HeLa expression library. The nucleotide sequence was 99% identical to MPP1, a cell-cycle-related nuclear protein phosphorylated during mitosis. Expression of the cDNA in an in vitro translation system yielded a recombinant protein that migrated in SDS-PAGE at approximately 97 kd. This protein was immunoprecipitated by the prototype human serum, by an immune guinea pig anti-MPP1 serum, but not by normal human serum or preimmune guinea pig serum. Western blot analysis of HeLa cell proteins showed that the prototype human serum and immune guinea pig antiserum recognized an approximately 225-kd protein, suggesting that the isolated clone contained a partial cDNA. By indirect immunofluorescence, the affinity-purified antibody and a guinea pig antiserum reacted with nuclei of interphase HEp-2 cells and the cytoplasm of certain neuronal cells. Sera from 10 of 25 unselected patients with ataxia, 1 of 30 patients with peripheral neuropathy, 1 of 50 multiple sclerosis patients, 0 of 20 amyotrophic lateral sclerosis, 0 of 10 children with postviral ataxia, 0 of 10 systemic lupus erythematosus patients, 0 of 3 patients with hereditary cerebellar ataxia, 0 of 8 with ataxia telangiectasia, and 0 of 30 age- and gender-matched controls immunoprecipitated the recombinant MPP1 protein. None of the patients with anti-MPP1 antibodies had evidence of malignancy. This is the first report of MPP1 as a target autoantigen in patients with idiopathic ataxia.
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PMID:Autoantibodies from patients with idiopathic ataxia bind to M-phase phosphoprotein-1 (MPP1). 1069 67

Lanthanides can contribute a large anomalous component to X-ray scattering when present and ordered in a target crystal. This large anomalous signal is a useful source of phase information in X-ray crystallographic studies of biological macromolecules. Thiol-reactive lanthanide chelates were tested as a means of incorporation of lanthanides into protein crystals. Two compounds, each capable of being loaded with a lanthanide of choice, were synthesized: diethylenetriaminepentaacetic 3-(2-pyridyldithio)propionyl hydrazide (DTPA-PDPH) and 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic 3-(2-pyridyldithio)propionyl hydrazide (DOTA-PDPH). A cysteine mutant of the 34 kDa phosphate-binding protein (PBP-A197C) from Escherichia coli was used as a test case. PBP-A197C was labeled with DTPA-PDPH loaded with dysprosium. Characteristics of DTPA-PDPH enabled spectroscopic monitoring of the labeling reaction. Complete labeling of PBP-A197C was confirmed by mass spectrometry and SDS-PAGE analysis. Labeled PBP-A197C (PBP-A197C-DTPA-Dy) crystallized identically to unlabeled protein. X-ray diffraction data were collected from PBP-A197C-DTPA-Dy crystals in-house with a Cu Kalpha rotating-anode source and with a tuneable synchrotron source (ALS 5.0.2). Synchrotron data were collected at energies corresponding to the Dy L(III) edge f" peak and a high-energy remote. Each data set was treated as an independent SAD experiment. A large anomalous signal was present in the data collected in-house and at the synchrotron. The Dy site was easily located in anomalous difference Patterson maps calculated from each of the data sets. In each case, SAD phasing resulted in high-quality electron-density maps, as evidenced by the success of automated model building. The generality of the method was analyzed with several other test proteins. Labeling of some of these proteins with thiol-reactive lanthanide chelates was deleterious to protein solubility or crystallization. In two of the cases the lanthanide chelate was disordered in the crystals. These results suggest that this method may not be well suited for high-throughput crystallography. However, for difficult cases requiring a large anomalous signal, thiol-reactive lanthanide chelates may prove to be a valuable tool.
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PMID:Thiol-reactive lanthanide chelates for phasing protein X-ray diffraction data. 1207 30

Accumulating evidence indicates that abnormal conformation of mutant superoxide dismutase 1 (SOD1) is an essential feature underlying the pathogenesis of mutant SOD1-linked familial amyotrophic lateral sclerosis (ALS). Here we investigated the role of ubiquitin-proteasome pathway in the mutant SOD1-related cell death and the effect of oxidative stress on the misfolding of mutant SOD1. Transient overexpression of ubiquitin with human SOD1 (wild-type, ala4val, gly85arg, gly93ala) in Neuro2A cells decreased the amount of mutant SOD1, but not of wild-type, while only mutants were co-immunoprecipitated with poly-ubiquitin. Proteasome inhibition by lactacystin augmented accumulation of mutant SOD1 in the non-ionic detergent-insoluble fraction. The spinal cord lysates from mutant SOD1 transgenic mice showed multiple carbonylated proteins, including mutant SOD1 with SDS-resistant dimer formation. Furthermore, the treatment of hSOD1-expressing cells with hydrogen peroxide promoted the oligomerization, and detergent-insolubility of mutant SOD1 alone, and the oxidized mutant SOD1 proteins were more heavily poly-ubiquitinated. In Neuro2A cells stably expressing human SOD1 protein, the proteasome function measured by chymotrypsin-like activity, was decreased over time without a quantitative alteration of the 20S proteasomal component. Finally, primary motor neurons from the mouse embryonic spinal cord were more vulnerable to lactacystin than non-motor neurons. These results indicate that the sustained expression of mutant SOD1 leads to proteasomal inhibition and motor neuronal death, which in part explains the pathogenesis of mutant SOD1-linked ALS.
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PMID:Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis. 1243 74

A long-chain derivative of 1,3-dioxolane sodium propyloxy sulfate, with similar denaturing and electrophoretic properties as SDS, and facilitated protein identification following polyacrylamide gel electrophoresis (PAGE) for Coomassie-stained protein bands, has been tested. Comparative acid-labile surfactant/sodium dodecyl sulfate two-dimensional (ALS/SDS 2-D)-PAGE experiments of lower abundant proteins from the proteomes of regenerating rat retina and mouse brain show that peptide recovery for mass spectrometry (MS) mapping is significantly enhanced using ALS leading to more successful database searches. ALS may influence some procedures in proteomic analysis such as the determination of protein content and methods need to be adjusted to that effect. The promising results of the use of ALS in bioanalytics call for detailed physicochemical investigations of surfactant properties.
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PMID:Sodium dodecyl sulfate versus acid-labile surfactant gel electrophoresis: comparative proteomic studies on rat retina and mouse brain. 1260 47

A major cytopathological hallmark of amyotrophic lateral sclerosis (ALS) is the presence of axonal spheroids containing abnormally accumulated neurofilaments. The mechanism of their formation, their contribution to the disease, and the possibility of other co-aggregated components are still enigmatic. Here we analyze the composition of such lesions with special reference to stable tubule only polypeptide (STOP), a protein responsible for microtubule cold stabilization. In normal human brain and spinal cord, the distribution of STOP proteins is uniform between the cytoplasm and neurites of neurons. However, all the neurofilament-rich spheroids present in the tissues of affected patients are intensely labeled with 3 different anti-STOP antibodies. Moreover, when neurofilaments and microtubules are isolated from spinal cord and brain, STOP proteins are systematically co-purified with neurofilaments. By SDS-PAGE analysis, no alteration of the migration profile of STOP proteins is observed in pathological samples. Other microtubular proteins, like tubulin or kinesin, are inconstantly present in spheroids, suggesting that a microtubule destabilizing process may be involved in the pathogenesis of ALS. These results indicate that the selective co-aggregation of neurofilament and STOP proteins represent a new cytopathological marker for spheroids.
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PMID:Stable tubule only polypeptides (STOP) proteins co-aggregate with spheroid neurofilaments in amyotrophic lateral sclerosis. 1469 97

High molecular weight detergent-insoluble complexes of superoxide dismutase 1 (SOD1) enzyme are a biochemical abnormality associated with mutant SOD1-linked familial amyotrophic lateral sclerosis (FALS). In the present study, SOD1 protein from spinal cords of transgenic FALS mice was fractionated according to solubility in saline, zwitterionic, non-ionic or anionic detergents. Both endogenous mouse SOD1 and mutant human SOD1 were least soluble in SDS, followed by NP-40 and CHAPS, with an eight-fold greater detergent resistance of mutant protein overall. Importantly, high molecular weight mutant SOD1 complexes were isolated with SDS-extraction only. To reproduce SOD1 aggregate pathology in vitro, primary fibroblasts were isolated and cultured from neonatal transgenic FALS mice. Fibroblasts expressed abundant mutant SOD1 without spontaneous aggregation over time with passage. Proteasomal inhibition of cultures using lactacystin induced dose-dependent aggregation and increased the SDS-insoluble fraction of mutant SOD1, but not endogenous SOD1. In contrast, paraquat-mediated superoxide stress in fibroblasts promoted aggregation of endogenous SOD1, but not mutant SOD1. Treatment of cultures with peroxynitrite or the copper chelator diethyldithiocarbamate (DDC) alone did not modulate aggregation. However, DDC inhibited lactacystin-induced mutant SOD1 aggregation in transgenic fibroblasts, while exogenous copper slightly augmented aggregation. These data suggest that SOD1 aggregates may derive from proteasomal or oxidation-mediated oligomerisation pathways from mutant and endogenous subunits respectively. Furthermore, these pathways may be affected by copper availability. We propose that non-neural cultures such as these transgenic fibroblasts with inducible SOD1 aggregation may be useful for rapid screening of compounds with anti-aggregation potential in FALS.
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PMID:Inducible superoxide dismutase 1 aggregation in transgenic amyotrophic lateral sclerosis mouse fibroblasts. 1503 41


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