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 have previously shown that the brains of patients with Alzheimer's disease (AD) express transforming growth factor (TGF)-beta 2 in neurofibrillary tangle (NFT)-bearing neurons and reactive astrocytes. The present study was undertaken to determine whether other neurodegenerative diseases were also associated with an alteration of the TGF-beta's. The immunohistochemical expression of TGF-beta 1, -2 and -3 was assessed in the brains of patients with progressive supranuclear palsy (n = 2), amyotrophic lateral sclerosis (n = 3), Lewy body disease (n = 5), Parkinson's disease (n = 1), Shy-Drager syndrome (n = 1), Pick's disease (n = 3), lobar atrophy (n = 1), and corticobasal degeneration (n = 2). Our results were compared to norms for controls (n = 8). We found expression of TGF-beta 2 in both NFT bearing neurons and tangle-bearing glial cells in progressive supranuclear palsy and in neurons with age-related NFT formation. Widespread staining of reactive astrocytes for TGF-beta 2 was observed in all degenerative diseases. TGF-beta 1 and -3 staining was not selectively altered in these diseases. We conclude that induction of TGF-beta 2 may be an intrinsic part of the processes that underlie NFT formation and reactive gliosis in a variety of neurodegenerative diseases.
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PMID:Transforming growth factor-beta: neuronal and glial expression in CNS degenerative diseases. 884 36

At present an increase of some autoaggressive diseases can be observed. The commonly used treatment consists of the administration of some immunosuppressive drug of some hormonal preparations. This type of therapy is accompanied by some undesired side effects, as these drugs influence also some other cell systems besides the immunologically active cells. These drugs are also known to lower the resistance to some intercurrent infections. Due to these undesired side effects some naturally occurring factors are introduced into the therapy. These are e.g., TGF-beta, or some interleukins (IL-10 etc.). In our department and immunosuppressively acting substance was isolated from DHL which had the ability to inhibit the AA (adjuvant arthritis) in rats. In humans this SF (suppressive factor) stimulates the CD 8+ cells which are known to have suppressoric activity. This SF was successfully applied in some autoaggressive diseases, e.g., atopic eczema, multiple sclerosis, some polyradiculoenuritis, amyotropic lateral sclerosis etc. In this paper the results in the ALS patients are given. Amongst other possibilities of the therapy the application of antilymphocyte sera, monoclonal antibodies to some CD markers of lymphocytes and some methods of hyposensitizations of tolerance induction are mentioned. Further, an original method using antigen bound to isosoluble carrier is described. This administration of encephalitogen bound onto Sforon (polyacrylate spheres) sis not only inhibit the EAE manifestations but also enable the survival of guinea-pigs which had already manifested the clinical signs of EAE.
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PMID:[Control of autoimmune processes by natural and other non-harmful methods]. 933 22

The transforming growth factor betas (TGF-betas) are multifunctional growth factors that act on both fibroblasts and myosatellite cells. In rodent models of muscle diseases, high levels of TGF-beta2 are expressed by myogenic cells. We have examined whether the expression of TGF-beta2 is also elevated in diseased human muscles. The disorders examined were Duchenne muscular dystrophy, myotonic dystrophy, myotubular myopathy, spinal muscular atrophy, and amyotrophic lateral sclerosis. The levels of TGF-beta2 immunoreactivity were elevated in atrophic, necrotic, and regenerating fibers and in fibers with central nuclei or cytoplasmic masses, irrespective of whether fibrosis was present. We therefore suggest that TGF-beta2 is important for muscle repair and that the presence of a TGF-beta within a muscle only leads to fibrosis if certain other factors are present.
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PMID:Transforming growth factor-beta2 is elevated in skeletal muscle disorders. 1039 7

Previous investigations have shown that the transforming growth factor-beta 1 (TGF-beta 1) may protect neurons against excitotoxic and oxidative damage and may inhibit apoptosis. The aim of this study was to investigate the role of TGF-beta 1 in patients with amyotrophic lateral sclerosis (ALS). The study involved 24 ALS patients and 15 control group people. The ALS patients were divided into groups according to their clinical status, and duration of ALS. The TGF-beta 1 in the serum and cerebrospinal fluid (CSF) was measured by the enzyme-linked immunosorbent assay (ELISA). Results showed that TGF-beta 1 concentrations in the serum, and CSF in the whole group of ALS patients did not differ from those of the controls, but the serum TGF-beta 1 concentration was significantly higher in ALS patients with a terminal clinical status than in controls. The TGF-beta 1 concentration was significantly higher in the CSF of the patients, with a long duration of ALS, than in the patients with a short duration of ALS, and there was a significant positive correlation between the CSF TGF-beta 1 and the duration of ALS. TGF-beta 1 may play a role in neurodegeneration of ALS, and may be an indicator of the duration of the disease.
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PMID:Transforming growth factor-Beta 1 (tgf-Beta 1) in patients with amyotrophic lateral sclerosis. 1255 Jan 9

Immunophilins are receptors for immunosuppressive drugs like cyclosporin A, FK506, rapamycin and their non- immunosuppressive analogs, which are collectively referred to as "immunophilin ligands" (IPL). Cyclosporin A binds to a class of IP called cyclophilins, whereas the receptors for FK506 and rapamycin belong to the family of FK506- binding proteins (FKBP). The latter are designated according to their molecular weight: FKBP12, 25, 52 etc. FKBP levels in the rat brain are up to 50 times higher than in the immune system. FKBP12 is associated with IP3 and ryanodine receptors present on the endoplasmic reticulum and plays a role in stabilizing calcium release. It has also been proposed to be a modulator of the TGFbeta receptor activity. Crush injury of facial or sciatic nerves in rat leads to markedly increased FKBP12 levels in the respective nerve nuclei and this increase is related to nerve regeneration. Cyclophilin A protects cells from death following expression of mutant Cu/ Zn superoxide dismutase, which is associated with familial amyotrophic lateral sclerosis. Our recent studies show that FKBP12 and FKBP52 are expressed in the human nervous system, especially in the substantia nigra- deep gray matter axis. In neurodegenerative diseases, FKBP12 levels increase in neurons situated in areas of pathology. This IP colocalizes with synaptophysin and alpha- synuclein, suggesting that it may become a novel marker of pathology. Immunophilins participate in axonal transport, synaptic vesicle assembly and may play a role in neuroprotection against abnormal protein aggregation, suggesting a potential avenue of therapeutic interventions.
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PMID:Immunophilins in nervous system degeneration and regeneration. 1287 Nov 69

Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson's disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer's disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.
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PMID:Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. 1765 32

Phosphorylated Smad2/3 (pSmad2/3), the central mediators of transforming growth factor (TGF)-beta signaling, were recently identified in tau-positive inclusions in certain neurodegenerative disorders. To clarify whether the localization of pSmad2/3 is altered in amyotrophic lateral sclerosis (ALS), we immunohistochemically examined spinal cords from sporadic ALS (SALS), from familial ALS (FALS) patients with the A4V mutation in their Cu/Zn superoxide dismutase (SOD1) gene, and from G93A mutant SOD1 transgenic (mSOD1 Tg) mice. In control spinal cords, pSmad2/3 immunoreactivity was observed exclusively in neuronal and glial nuclei. In SALS and FALS patients the nuclei showed increased immunoreactivity for pSmad2/3. Noticeably, round hyaline inclusions (RHIs) and skein-like inclusions of SALS patients were immunoreactive for pSmad2/3. Double immunofluorescence staining for pSmad2/3 and transactive response-DNA-binding protein (TDP)-43 revealed co-localization of these proteins within RHIs. In contrast, Bunina bodies in SALS and Lewy body-like hyaline inclusions (LBHIs) in FALS were devoid of labeling for pSmad2/3. Similarly, in the mSOD1 Tg mice pSmad2/3 immunoreactivity was increased in the nuclei, while LBHIs were not labeled. These findings suggest increased TGF-beta-Smad signaling in SALS, FALS, and mSOD1 Tg mice, as well as impaired TGF-beta signal transduction in RHI-bearing neurons of SALS patients, presumably at the step of pSmad2/3 translocation into the nucleus. The pathomechanisms, including the process of inclusion development, appears to be different between SALS and mSOD1-related FALS or Tg mice.
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PMID:Phosphorylated Smad2/3 immunoreactivity in sporadic and familial amyotrophic lateral sclerosis and its mouse model. 1821 Jan 39

Amyotrophic lateral sclerosis (ALS) is a neurologic disease characterized by progressive weakness that results in death within a few years of onset by respiratory failure. Myostatin is a member of the TGF-beta superfamily that is predominantly expressed in muscle and acts as a negative regulator of muscle growth. Attenuating myostatin has previously been shown to produce increased muscle mass and strength in normal and disease animal models. In this study, a mouse model of ALS (SOD1(G93A) transgenic mice) was treated with a soluble activin receptor, type IIB (ActRIIB.mFc) which is a putative endogenous signaling receptor for myostatin in addition to other ligands of the TGF-beta superfamily. ActRIIB.mFc treatment produces a delay in the onset of weakness, an increase in body weight and grip strength, and an enlargement of muscle size whether initiated pre-symptomatically or after symptom onset. Treatment with ActRIIB.mFc did not increase survival or neuromuscular junction innervation in SOD1(G93A) transgenic mice. Pharmacologic treatment with ActRIIB.mFc was superior in all measurements to genetic deletion of myostatin in SOD1(G93A) transgenic mice. The improved function of SOD1(G93A) transgenic mice following treatment with ActRIIB.mFc is encouraging for the development of TGF-beta pathway inhibitors to increase muscle strength in patients with ALS.
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PMID:A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis. 1928 73

Human bone marrow stromal cells (BM-SCs) possess the potential to differentiate, self-renew, and produce diverse trophic/growth factors and are an excellent cell therapy tool for degenerative diseases. However, they exhibit different therapeutic efficacies, depending on the health status and age of the cell donor. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron death in the central nervous system. In this study, we isolated BM-SCs from 11 ALS patients and characterized their potential secretory capacity of neurotrophic factors. We identified significant reductions in the expression of Oct-4 and Nanog , and in the trophic factors ANG, FGF -2, HGF, IGF-1, PIGF, SDF-1alpha , TGF-beta, and VEGF, but not in BDNF or ECGF. Migration of ALS-SCs was reduced, although the cells expressed the same markers for human mesenchymal phenotypes. These data suggest that ALS-SCs have diminished capacity as trophic mediators and may have reduced beneficial effects in cell therapy.
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PMID:Bone marrow-derived stromal cells from amyotrophic lateral sclerosis patients have diminished stem cell capacity. 2003 May 61