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)

A population of T cells sensitive to ALS treatment release a non-specific factor (NSF) capable of replacing T cells in the response of nude spleen cells to erythrocyte antigens. This factor cannot be removed by immunoadsorbents with specificities directed towards products of the H2 complex, nor by lentil lectin, unlike certain specific T-cell factors. Furthermore, it functions across histocompatibility differences between mouse strains. It has been directly demonstrated that this factor can influence both proliferation and differentiation of B cells in response to a restricted group of T-dependent antigens, of which donkey and sheep erythrocytes are such special cases.
 ...
PMID:Antigen-non-specific T-cell factor in B-cell activation. Origin, biological properties and failure to show a relationship to H-2. 5 34

Some heavy metals have been suspected of playing a role in the pathogenesis of nervous system diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. In these disorders, autoantibodies against neural proteins are evident at some stage of the disease. Lead is known to affect both the immune and nervous systems. Work in our laboratory has shown that lead exposure leads to the production of autoantibodies against neural proteins, including myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP). We hypothesize that lead aggravates neurological disease by enhancing the immunogenicity of nervous system proteins, including MBP and GFAP. To test this hypothesis, lead-altered protein was prepared by incubating MBP or GFAP with lead acetate for 24 hr. On days 0, 14, and 28, mice received inoculations with either saline, native protein, or lead-altered protein. Anti-MBP and anti-GFAP, isotypes IgM and IgG, were measured in sera by ELISA on day 38. Sera of mice treated with lead-altered MBP had statistically higher anti-MBP IgG titers than both control and native MBP-immunized mice. An analogous response was seen in mice immunized with lead-altered GFAP. Supernatants from lectin-stimulated splenocytes were also examined for antibody titers and for interleukin 2 (IL-2) and interleukin 6 (IL-6) levels. A significant increase in IL-6 production was seen in mice immunized with lead-altered MBP but not with lead-altered GFAP. No changes were observed in the IL-2 levels of mice immunized with either lead-altered protein.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Lead alters the immunogenicity of two neural proteins: a potential mechanism for the progression of lead-induced neurotoxicity. 753 56

Lectins, glycine max (SBA) and Vicia villosa (VVA), which identify terminal N-acetyl-D-galactosamine (GalNAc), stained the motor neurons of a patient with subacute motor neuronopathy associated with neoplastic angioendotheliosis. In normal controls and in patients with other neurological disorders including amyotrophic lateral sclerosis, neither lectin stained motor neurons. Abnormal glycosylation of motor neurons with terminal galNAc may be associated with the pathogenesis of subacute motor neuronopathy in this patient.
 ...
PMID:Abnormal glycosylation of motor neurons with N-acetyl-D-galactosamine in a case of subacute motor neuronopathy associated with lymphoma. 793 31

Glycoconjugates in the serum of 73 patients with amyotrophic lateral sclerosis (ALS), 21 cases of other motor neuron diseases and 20 healthy controls were determined. Cerebrospinal fluid (CSF) was studied in 64, 7 and 10 of these subjects, respectively. The level of sialic acid containing glycoconjugates, detected by Maakia amurensis agglutinin (MAA), was decreased in the serum of 61.6% of the ALS patients, while in the CSF it was decreased, on average, in 75% of these cases. Only in single ALS cases was the concentration of these glycoconjugates increased. There was no correlation between the content of MAA-labelled glycoconjugates both in serum and CSF and the titre of sialic acid containing anti-GM1 gangliosides. The glycoconjugates, detected by peanut agglutinin (PNA) which recognizes the disaccharide galactose beta(1-3)N- acetylgalactosamine (GGN), were decreased in the serum of 78.1% of ALS patients, while in CSF they were increased in 54.7% of these cases. There was no correlation between the concentration of PNA-labelled glycoconjugates both in serum and CSF as well as the titre of antibodies against GGN-containing anti-GM1 and anti- AGM1 gangliosides. Changes in the level of the MAA- and PNA- labelled glycoconjugates, as well as the titre of anti-GM1 and anti-AGM1 gangliosides antibodies were not specific for ALS. They were also observed in some cases of other motor neuron diseases. The low level of the lectin-labelled glycoconjugates in serum and partly in CSF of the majority of ALS patients is possibly the consequence of their accelerated clearance and/or specific inactivation by the formation of immune complexes or epitope binding. Degeneration of neurons and muscle cells could also be responsible. The relatively low incidence of high anti- glycolipids antibodies titre may be, at least partly, connected with the low concentration of the appropriate antigens. The increased content of PNA-labelled glycoconjugates in the CSF of the majority of ALS patients, together with the low incidence of high titre of antibodies against the appropriate glycolipids, could indicate that in CSF this lectin binds to the GGN epitope of glycoproteins rather than to the GGN epitope of glycolipids.
 ...
PMID:Immunochemical quantification of glycoconjugates in serum and cerebrospinal fluid of amyotrophic lateral sclerosis patients. 1021 Sep 15

Mice over-expressing a human mutation of Cu(2+)/Zn(2+) superoxide dismutase (SOD1) provide a model of amyotrophic lateral sclerosis. Using tomato lectin histochemistry, we analyzed microglia in the facial nuclei of SOD1(G93A) transgenic mice in the late stage of disease. In these animals, microglia was markedly activated, and ensheathed facial motoneurons as observed in wild-type mice 1 week after nerve transection. In the axotomized facial nucleus of transgenic mice at the same time point, microglia activation was enhanced and exhibited phagocytic features. The findings show that in the facial nucleus microglial cells react to motoneuron disease caused by the SOD1 mutation and to axotomy-induced damage of facial motoneurons.
 ...
PMID:Activation and response to axotomy of microglia in the facial motor nuclei of G93A superoxide dismutase transgenic mice. 1079 33

Enriched populations of human microglial cells were isolated from mixed cell cultures prepared from embryonic human telencephalon tissues. Human microglial cells exhibited cell type-specific antigens for macrophage-microglia lineage cells including CD11b (Mac-1), CD68, B7-2 (CD86), HLA-ABC, HLA-DR and ricinus communis aggulutinin lectin-1 (RCA-1), and actively phagocytosed latex beads. Gene expression and protein production of cytokines, chemokines and cytokine/chemokine receptors were investigated in the purified populations of human microglia. Normal unstimulated human microglia expressed constitutively mRNA transcripts for interleukin- 1beta (IL-1beta) -6, -8, -10, -12, -15, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and monocyte chemoattractant protein-1 (MCP-1), while treatment with lipopolysaccharide (LPS) or amyloid beta peptides (Abeta) led to increased expression of mRNA levels of IL-8, IL-10, IL-12, TNF-alpha, MIP-1alpha, MIP-1beta, and MCP-1. Human microglia, in addition, expressed mRNA transcripts for IL-1RI, IL-1RII, IL-5R, IL-6R, IL-8R, IL-9R, IL-10R, IL-12R, IL-13R, and IL-15R. Enzyme-linked immunosorbent assays (ELISA) showed increased protein levels in culture media of IL-1beta, IL-8, TNF-alpha, and MIP-1alpha in human microglia following treatment with LPS or Abeta. Increased TNF-alpha release from human microglia following LPS treatment was completely inhibited with IL-10 pretreatment, but not with IL-6, IL-9, IL-12, IL-13, or transforming growth factor-beta (TGF-beta). Present results should help in understanding the basic microglial biology, but also the pathophysiology of activated microglia in neurological diseases such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, stroke, and neurotrauma.
 ...
PMID:Cytokines, chemokines, and cytokine receptors in human microglia. 1211 20

Previous data have suggested that galectin-1 is expressed widely in nervous tissues at embryonic stages but becomes restricted mainly to peripheral nervous tissues with maturation. Though the expression is intense in adult mammalian peripheral neurons, there had been no report about functions of galectin-1 there. Recently we discovered a factor that enhanced peripheral axonal regeneration. The factor was identified as oxidized galectin-1 with three intramolecular disulfide bonds and showed no lectin activity. Oxidized recombinant human galectin-1 (rhGAL-1/Ox) showed the same nerve growth promoting activity at very low concentrations (pg/ml). rhGAL-1/Ox at similarly low concentration was also effective in in vivo experiments of axonal regeneration. Moreover, the application of functional anti-rhGAL-1 antibody strongly inhibited the axonal regeneration in vivo as well as in vitro. Since galectin-1 is expressed in the regenerating sciatic nerves as well as in both sensory neurons and motor neurons, these results suggest that galectin-1 is secreted into the extracellular space to be oxidized, and then, in its oxidized form, to regulate initial repair after axotomy. The administration of oxidized galectin-1 effectively promoted functional recovery after sciatic nerve injury in vivo. Oxidized galectin-1, hence, appears to play an important role in promoting axonal regeneration, working as a kind of cytokine, not as a lectin. Recent reports indicated additional roles of cytosolic galectin-1 in neural diseases, such as ALS. Furthermore galectin-1 has been proved to be a downstream target of DeltaFosB. In hippocampus of rat brain, expression of DeltaFosB is induced immediately after ischemia-reperfusion, suggesting that galectin-1 may also play important roles in central nervous system after injury.
 ...
PMID:Galectin-1 plays essential roles in adult mammalian nervous tissues. Roles of oxidized galectin-1. 1475 71

This study characterizes a model of motor neuron (MN) loss on the molecular, cellular, and behavioral levels. Injection of the toxic lectin Ricinus communis agglutinin I (RCA I or ricin) caused cellular deficit and loss of function by damaging the sciatic nerve. Since the sciatic nerve supplies movement to most of the lower limb, damaging this motor system models lower limb paralysis and the deficits that occur in diseases like amyotrophic lateral sclerosis (ALS) and infantile progressive spinal muscular atrophy (SMA). We used motor-, sensorimotor-, locomotor-, and reflex-based tests to demonstrate loss of function after ricin injection. Loss of function was also demonstrated by decreased retrograde transport, and supported by measurements of muscle wasting. Histochemical and molecular methods were used to characterize sciatic nerve damage in axons and cell bodies, including apoptotic cell death in MNs. This battery of tests documents the extent of the ricin-induced damage and provides a baseline that can be used to judge the efficacy of MN treatment strategies in preclinical studies.
 ...
PMID:A model of motor neuron loss: selective deficits after ricin injection. 2048 2

Amyotrophic lateral sclerosis (ALS) is a devastating, neurodegenerative motor neuron disease. The aetiology of ALS remains an enigma which hinders the design of an effective treatment to prevent, postpone, or reverse the pathophysiological changes occurring during the aggressive progression of this disease. During the last decade, basic research within the innate immune system, and in particular the complement system, has revealed new, important roles of the innate immune system during development, homeostasis, and ageing within as well as outside the central nervous system. Several lines of evidence indicate that aberrant activation of the complement system locally in the central nervous system as well as systemically may be involved in the pathophysiology of ALS. This exciting new knowledge could point towards the innate immune system as a potential target of medical intervention in ALS. Recently, the historic perception of ALS as a central neurodegenerative disease has been challenged due to the significant amount of evidence of a dying-back mechanism causing the selective destruction of the motor neurons, indicating that disease onset occurs outside the borders of the blood-brain-barrier. This review addresses the function of the innate immune system during ALS. We emphasize the role of the complement system and specifically suggest the involvement of ficolin-3 from the lectin pathway in the pathophysiology of ALS.
 ...
PMID:Amyotrophic lateral sclerosis: The complement and inflammatory hypothesis. 2993 90

Macroautophagy/autophagy, a defense mechanism against aberrant stresses, in neurons counteracts aggregate-prone misfolded protein toxicity. Autophagy induction might be beneficial in neurodegenerative diseases (NDs). The natural compound trehalose promotes autophagy via TFEB (transcription factor EB), ameliorating disease phenotype in multiple ND models, but its mechanism is still obscure. We demonstrated that trehalose regulates autophagy by inducing rapid and transient lysosomal enlargement and membrane permeabilization (LMP). This effect correlated with the calcium-dependent phosphatase PPP3/calcineurin activation, TFEB dephosphorylation and nuclear translocation. Trehalose upregulated genes for the TFEB target and regulator Ppargc1a, lysosomal hydrolases and membrane proteins (Ctsb, Gla, Lamp2a, Mcoln1, Tpp1) and several autophagy-related components (Becn1, Atg10, Atg12, Sqstm1/p62, Map1lc3b, Hspb8 and Bag3) mostly in a PPP3- and TFEB-dependent manner. TFEB silencing counteracted the trehalose pro-degradative activity on misfolded protein causative of motoneuron diseases. Similar effects were exerted by trehalase-resistant trehalose analogs, melibiose and lactulose. Thus, limited lysosomal damage might induce autophagy, perhaps as a compensatory mechanism, a process that is beneficial to counteract neurodegeneration. Abbreviations: ALS: amyotrophic lateral sclerosis; AR: androgen receptor; ATG: autophagy related; AV: autophagic vacuole; BAG3: BCL2-associated athanogene 3; BECN1: beclin 1, autophagy related; CASA: chaperone-assisted selective autophagy; CTSB: cathepsin b; DAPI: 4',6-diamidino-2-phenylindole; DMEM: Dulbecco's modified Eagle's medium; EGFP: enhanced green fluorescent protein; fALS, familial amyotrophic lateral sclerosis; FRA: filter retardation assay; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GLA: galactosidase, alpha; HD: Huntington disease; hIPSCs: human induced pluripotent stem cells; HSPA8: heat shock protein A8; HSPB8: heat shock protein B8; IF: immunofluorescence analysis; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; LGALS3: lectin, galactose binding, soluble 3; LLOMe: L-leucyl-L-leucine methyl ester; LMP: lysosomal membrane permeabilization; Lys: lysosomes; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MCOLN1: mucolipin 1; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; NDs: neurodegenerative diseases; NSC34: neuroblastoma x spinal cord 34; PBS: phosphate-buffered saline; PD: Parkinson disease; polyQ: polyglutamine; PPARGC1A: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PPP3CB: protein phosphatase 3, catalytic subunit, beta isoform; RT-qPCR: real-time quantitative polymerase chain reaction; SBMA: spinal and bulbar muscular atrophy; SCAs: spinocerebellar ataxias; siRNA: small interfering RNA; SLC2A8: solute carrier family 2, (facilitated glucose transporter), member 8; smNPCs: small molecules neural progenitors cells; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; STED: stimulated emission depletion; STUB1: STIP1 homology and U-box containing protein 1; TARDBP/TDP-43: TAR DNA binding protein; TFEB: transcription factor EB; TPP1: tripeptidyl peptidase I; TREH: trehalase (brush-border membrane glycoprotein); WB: western blotting; ZKSCAN3: zinc finger with KRAB and SCAN domains 3.
 ...
PMID:Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration. 3033 91


1