Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We synthesized 3 peptide fragments predicted by residues 2354-2368 (peptide I), 2310-2324 (peptide II) and 2255-2269 (peptide III) on the mid-portion of the human dystrophin cDNA map where the most frequent intragenic deletions occurred in Duchenne muscular dystrophy. Rabbit antibodies against these peptides were raised and cryosections of 47 biopsied muscles were studied immunohistochemically. The 47 biopsied muscles included the quadriceps femoris muscles of 8 Duchenne muscular dystrophy patients, 8 child and 5 adult normal controls, 1 facioscapulohumeral dystrophy, 2 limb girdle dystrophy, 3 myotonic dystrophy, 3 polymyositis, 1 mitochondrial myopathy, 1 nemaline myopathy, 3 amyotrophic lateral sclerosis and the extensor digitorum longus muscles of 6 mdx mice (C57BL/10ScSn-mdx) and 6 normal control mice (C57BL/10ScSn). The peptide I antiserum continuously stained the myofiber surface membranes in 8 child and 5 adult normal control muscles, and in 14 other muscles from various neuromuscular diseases, but failed to stain the surface membranes in normal control mice. The surface membranes of 8 Duchenne muscles were not stained by the peptide I antiserum except for a few myofibers. Although the ELISA titers of peptide I, II and III antibodies were high, immunostaining by peptide II antiserum showed no reaction in the myofibers of any of the biopsied muscles, and immunostaining by peptide III antiserum revealed faint reactions on the myofiber surface membranes of all biopsied muscles, including the mdx control mouse muscles except for the Duchenne and mdx myofibers.
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PMID:Immunoreactivity of antibodies raised against synthetic peptide fragments predicted from mid portions of dystrophin cDNA. 220 9

We used polyclonal antibodies against dystrophin for the immunohistochemical localization of this protein in human skeletal muscle. Dystrophin was localized in the sarcolemma of the myofibers in 8 infantile and 11 adult normal control muscles and in 10 early stage patient muscles with amyotrophic lateral sclerosis (ALS). The protein was absent or markedly decreased in 8 early stage patients with Duchenne muscular dystrophy (DMD). Moreover the densities of sarcolemmal plasma membrane assemblies, orthogonal arrays and their pits were estimated by freeze-fracture electron microscopy studies in the same number of muscle samples in each disease and control case. The group median densities of orthogonal arrays and their pits in the ALS group and adult control group were 4.8 with a midrange of 1.1-13.5 (25-75%) and 7.5 with a midrange of 2.3-12.9, respectively (P greater than 0.1, Wilcoxon rank-sum test), whereas those of the DMD group and child control group were 0 with a midrange of 0-1.1 and 10.8 with a midrange of 5.4-16.7 respectively (P less than 0.01). The skeletal muscles of mdx mice and their controls were also investigated by the same techniques. In mdx mice, the absence or marked deficiency of dystrophin was also noted; however, the decrease of orthogonal arrays was not as severe as in DMD, which might relate to the milder clinical features in mdx mice as compared with those in DMD.
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PMID:Dystrophin immunostaining and freeze-fracture studies of muscles of patients with early stage amyotrophic lateral sclerosis and Duchenne muscular dystrophy. 266 93

The changes of myoglobin localization in the skeletal muscle cells in Duchenne muscular dystrophy (DMD), myotonic dystrophy (MyD), and amyotrophic lateral sclerosis (ALS) were studied by immunohistochemistry and immunoelectron microscopy. In normal skeletal muscle cells, myoglobin was found in I band, Z line, mitochondrial outer membrane and inner membrane structures of sarcoplasmic reticulum and T tube. In contrast, the myoglobin staining of the I bands in degenerative muscle-cells of DMD and MyD was found rather diminished, and A bands, intraluminal spaces of the inner membrane system and intermyofibrillar spaces were myoglobin positive. Moreover, the I band of a myofibril which slipped out of other normally arranged myofibrils showed no myoglobin staining, but the distended intermyofibrillar spaces adjacent to the slipped myofibril showed a definite staining. In addition, there were dilated sarcoplasmic reticula showing the staining in their lumina, but the I bands neighboring them revealed a diminished staining. In DMD muscle, no staining was found in opaque fibers and some small sized fibers. In ALS muscle, myoglobin was usually positive in the I bands, but the small angulated fibers showed a variable staining. In the target fibers, central zone was not stained but intermediate zone showed altered myoglobin localization. These data indicate that (1) myoglobin localization in the muscle cells varies depending on the sorts of diseases and the grades of muscle cell degeneration, (2) myoglobin in dystrophic muscles fluxes from the muscle cells to extracellular spaces through the dilated sarcoplasmic reticula, T tubes and intermyofibrillar spaces, and (3) in DMD muscle, myoglobin also fluxes directly through the deteriorated plasma membrane in opaque fibers or through the plasma membrane altered due to dystrophin deficiency.
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PMID:[Changes in myoglobin localization in the skeletal muscle of neuromuscular diseases demonstrated by immunohistochemistry and immunoelectron microscopy]. 268 Feb 5

Normal human myoblasts were cloned and transplanted in the tibialis anterior of immunodeficient nude and SCID mice and in mdx mice under different immunosuppressive treatments (cyclosporine A, CsA; antilymphocyte serum, ALS) or not immunosuppressed. This permitted us to show the interaction of the immune system in the myoblast transplantation. The graft success was assessed by verifying signs of humoral and cellular immune reactions and the presence of dystrophin produced by the fusion of the donor myoblasts. This study showed that clones of human myoblasts were able to fuse and produce dystrophin in injected muscles of immunodeficient mice and mdx mice receiving an effective immunosuppressive treatment (i.e., ALS+CsA). However, the same pool of human myoblasts injected in mdx mice inadequately immunosuppressed (i.e., CsA alone or ALS alone) triggered an immune reaction and was rejected. Cells expressing CD4 and CD8 antigens were observed in the injected muscles of mice treated with CsA alone. Therefore, evidence of humoral and cellular rejection was observed following human myoblasts transplantation.
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PMID:Human myoblast transplantation in immunodeficient and immunosuppressed mice: evidence of rejection. 811 93

Thirty-four biopsied muscles of Duchenne, Becker and congenital muscular dystrophy, congenital myotonic dystrophy and amyotrophic lateral sclerosis were examined by an immunocytochemical method with an anti-dystrophin-related protein (DRP) antibody. Strongly positive immunoreaction to DRP at the neuromuscular junctions in all biopsied specimens and faint reaction on the surface membrane of atrophic fibers in amyotrophic lateral sclerosis suggest that DRP is an anchor protein of the acetylcholine receptor. Additionally, the surface membrane of muscle fibers of Duchenne muscular dystrophy was positively stained. DRP is, therefore, thought to be expressed to compensate for dystrophin deficiency in these muscle fibers.
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PMID:Dystrophin-related protein in skeletal muscles in neuromuscular disorders: immunohistochemical study. 846 May 31

We studied the densities of utrophin and dystrophin at the motor end-plates of patients with myasthenia gravis (MG) using immunohistochemical analysis. The densities were compared with those found in patients with amyotrophic lateral sclerosis, Lambert-Eaton myasthenic syndrome and normal controls. Utrophin was reduced at the motor end-plates of MG patients, in association with a reduction of alpha-bungarotoxin binding sites. In contrast, the density of dystrophin at the motor end-plate of MG patients was not significantly different from that found in the controls. We conclude that, at the motor end-plate, utrophin may be more closely associated than dystrophin with the acetylcholine receptor, and that it plays a different role.
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PMID:Immunohistochemical study of utrophin and dystrophin at the motor end-plate in myasthenia gravis. 881 Nov 20

To substantiate the role of nitric oxide synthase type-I (NOS-I) in neurogenic muscular disorders we investigated human biopsy samples of type-II fiber atrophy and amyotrophic lateral sclerosis (ALS) by NOS-I immunoreactivity (-IR), NOS-associated NADPH-dependent diaphorase activity (NOSaD) and Western blot analysis. In type-II atrophy, loss of NOSaD and reduced NOS-I-IR was apparent in atrophic myofibers. In atrophic fiber groups lacking NOSaD, both NOS-I and dystrophin-IR was decreased while sarcolemmal beta-dystroglycan- and adhalin-IR (markers of the sarcolemmal dystrophin-glycoprotein complex) was normal. In ALS, groups of scattered angulated atrophic fibers revealed partial loss of NOS-I-IR/NOSaD. Atrophied fibers of either type-I or type-II thus revealed differential sarcolemmal NOS/NOSaD pattern thereby reflecting myopathological alterations of the NO-system in human type-II atrophy and ALS.
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PMID:Partial loss of NADPH-diaphorase/nitric oxide synthase-complex in amyotrophic lateral sclerosis and human type-II myofiber atrophy. 930 Jun 47

Modern molecular biology has revealed vast numbers of large and complex proteins and genes that regulate body function. By contrast, discoveries over the past ten years indicate that crucial features of neuronal communication, blood vessel modulation and immune response are mediated by a remarkably simple chemical, nitric oxide (NO). Endogenous NO is generated from arginine by a family of three distinct calmodulin- dependent NO synthase (NOS) enzymes. NOS from endothelial cells (eNOS) and neurons (nNOS) are both constitutively expressed enzymes, whose activities are stimulated by increases in intracellular calcium. Immune functions for NO are mediated by a calcium-independent inducible NOS (iNOS). Expression of iNOS protein requires transcriptional activation, which is mediated by specific combinations of cytokines. All three NOS use NADPH as an electron donor and employ five enzyme cofactors to catalyze a five-electron oxidation of arginine to NO with stoichiometric formation of citrulline. The highest levels of NO throughout the body are found in neurons, where NO functions as a unique messenger molecule. In the autonomic nervous system NO functions NO functions as a major non-adrenergic non-cholinergic (NANC) neurotransmitter. This NANC pathway plays a particularly important role in producing relaxation of smooth muscle in the cerebral circulation and the gastrointestinal, urogenital and respiratory tracts. Dysregulation of NOS activity in autonomic nerves plays a major role in diverse pathophysiological conditions including migraine headache, hypertrophic pyloric stenosis and male impotence. In the brain, NO functions as a neuromodulator and appears to mediate aspects of learning and memory. Although endogenous NO was originally appreciated as a mediator of smooth muscle relaxation, NO also plays a major role in skeletal muscle. Physiologically muscle-derived NO regulates skeletal muscle contractility and exercise-induced glucose uptake. nNOS occurs at the plasma membrane of skeletal muscle which facilitates diffusion of NO to the vasculature to regulate muscle perfusion. nNOS protein occurs in the dystrophin complex in skeletal muscle and NO may therefore participate in the pathophysiology of muscular dystrophy. NO signalling in excitable tissues requires rapid and controlled delivery of NO to specific cellular targets. This tight control of NO signalling is largely regulated at the level of NO biosynthesis. Acute control of nNOS activity is mediated by allosteric enzyme regulation, by posttranslational modification and by subcellular targeting of the enzyme. nNOS protein levels are also dynamically regulated by changes in gene transcription, and this affords long-lasting changes in tissue NO levels. While NO normally functions as a physiological neuronal mediator, excess production of NO mediates brain injury. Overactivation of glutamate receptors associated with cerebral ischemia and other excitotoxic processes results in massive release of NO. As a free radical, NO is inherently reactive and mediates cellular toxicity by damaging critical metabolic enzymes and by reacting with superoxide to form an even more potent oxidant, peroxynitrite. Through these mechanisms, NO appears to play a major role in the pathophysiology of stroke, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.
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PMID:Endogenous nitric oxide synthesis: biological functions and pathophysiology. 1063 Jun 82

Previous investigators have suggested that proteolysis by calpain, a Ca2+-dependent protease, causes muscle fiber degradation in Duchenne and Becker muscular dystrophies (DMD/BMD). Recent evidence indicates that the nonlysosomal ATP-ubiquitin-dependent proteolytic complex (proteasomes) participates in muscle wasting during various catabolic states and in muscle fiber degradation in physiological or pathological conditions. To elucidate the possible role of proteasomes in dystrophic muscles, routine histochemistry and immunohistochemistry of 26S proteasomes were performed on muscle biopsy specimens obtained from patients with various neuromuscular disorders including DMD/BMD, polymyositis (PM), amyotrophic lateral sclerosis, and peripheral neuropathies, and on normal human muscle specimens. Immunohistochemically, proteasomes were located in the cytoplasm in normal human muscle, but their staining intensity was faint. Compared to control muscles, abnormal increases in both proteasomes and ubiquitin were demonstrated mainly in the cytoplasm of necrotic fibers and to a lesser extent in regenerative fibers in DMD/BMD and PM. Non-necrotic, atrophic fibers in all diseased muscles showed moderate or weak immunoreactions for the proteins; their staining intensities were stronger than those of control muscle fibers. Both proteins often colocalized well. Not all dystrophin-deficient muscle fibers showed a strong reaction for proteasomes. Our results showed increased proteasomes in necrotic and regenerative muscle fibers in DMD/ PMD, although this may not be disease-specific up-regulation. We suggest that the ATP-ubiquitin-dependent proteolytic pathway as well as the nonlysosomal calpain pathway may participate in muscle fiber degradation in muscular dystrophy.
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PMID:Proteasome expression in the skeletal muscles of patients with muscular dystrophy. 1107 10

Dystrophin and associated proteins form a complex with an important role at the sarcolemma. Expression of this protein complex is highly regulated during development and regeneration. In order to better understand assembling patterns of these proteins, we have studied their expression in targetoid-like phenomena found in human muscle after chronic denervation, a situation known to give rise to abnormal protein trafficking. In eight biopsies of patients with chronic denervation, mainly resulting from amyotrophic lateral sclerosis, we found a number of targetoid phenomena. Selective accumulation of a number of sarcolemmal and sarcoplasmatic proteins occurred in targetoid phenomena. The larger majority of them contained gamma-sarcoglycan (gammaSG), but none contained the developmental heavy chain myosin isoform. In a series of 166 targetoid phenomena which could be studied with 17 different antibodies recognizing sarcolemmal and cytoplasmatic proteins, a high level of colocalization of gammaSG with desmin and alpha-actinin was found. Colocalization rate was much lower with other proteins, including other members of the dystrophin-associated protein complex. These data show that selective changes in expression of otherwise closely related proteins occur during disturbed trafficking leading to target formation. Because members of the dystrophin-associated protein complex do not accumulate in a similar fashion within targets, we suggest that a complex molecular control of gene expression and trafficking of this complex is involved after chronic muscle denervation.
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PMID:Disturbed trafficking of dystrophin and associated proteins in targetoid phenomena after chronic muscle denervation. 1517 79


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