Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with amyotrophic lateral sclerosis possess antibodies (ALS IgGs) that bind to L-type skeletal muscle voltage-gated calcium channels (VGCCs) and inhibit L-type calcium current. To determine whether interaction of ALS IgGs with neuronal VGCCs might influence motoneuron survival, we used a motoneuron-neuroblastoma hybrid (VSC 4.1) cell line expressing binding sites for inhibitors of L-, N-, and P-type VGCCs. Using direct viable cell counts, quantitation of propidium iodide- and fluorescein diacetate-labeled cells, and lactate dehydrogenase release to assess cell survival, we document that ALS IgG kills 40-70% of cAMP-differentiated VSC 4.1 cells within 2 days. ALS IgG-mediated cytotoxicity is dependent on extracellular calcium and is prevented by peptide antagonists of N- or P-type VGCCs but not by dihydropyridine modulators of L-type VGCCs. Preincubating IgG with purified intact L-type VGCC or with isolated VGCC alpha 1 subunit also blocks ALS IgG-mediated cytotoxicity. These results suggest that ALS IgG may directly lead to motoneuron cell death by a mechanism requiring extracellular calcium and mediated by neuronal-type calcium channels.
...
PMID:Cytotoxicity of immunoglobulins from amyotrophic lateral sclerosis patients on a hybrid motoneuron cell line. 815 58

This work shows that the neurotoxic excitatory amino acids beta-N-methylamino alanine, BMAA, and kainate, modulate neurite outgrowth; this was assessed by measuring the levels of two separate neurofilament proteins (68 kD and 160 kD), in a mouse neuroblastoma cell line, (NB41A3). BMAA has been proposed to be the exogenous excitotoxin in Guam disease or amyotrophic lateral sclerosis (ALS/parkinsonian/dementia; Guam ALS-PD). Kainate is a glutamate analogue which causes excitotoxic damage associated with excessive entry of calcium into neurons. The results show that at low doses (10(-9) to 10(-7) M) both BMAA and kainate decrease the concentration of the two neurofilament proteins. However at high doses (10(-6) to 10(-5) M) they cause an apparent accumulation of the neurofilament proteins; the effect is more marked with BMAA. These results support the continued development of an in vitro test for neurotoxicity based on neurite outgrowth.
...
PMID:Use of neurite outgrowth as an in vitro method of assessing neurotoxicity. 851 88

It is generally agreed that ALS/PDC is triggered by a disappearing environmental factor peculiar to the lifestyle of people of the western Pacific (i.e., Guam, Irian Jaya, Indonesia, and the Kii Peninsula of Japan). A strong candidate is the cycad plant genotoxin cycasin, the beta-D-glucoside of methylazoxymethanol (MAM). We propose that prenatal or postnatal exposure to low levels of cycasin/MAM may damage neuronal DNA, compromise DNA repair, perturb neuronal gene expression, and irreversibly alter cell function to precipitate a slowly evolving disease ("slow-toxin" hypothesis). In support of our hypothesis, we have demonstrated the following: 1. DNA from postmitotic rodent central nervous system neurons is particularly sensitive to damage by MAM. 2. MAM reduces DNA repair in human and rodent neurons, whereas DNA-repair inhibitors potentiate MAM-induced DNA damage and toxicity in mature rodent nervous tissue. 3. Human neurons (SY5Y neuroblastoma) that are deficient in DNA repair are susceptible to MAM-induced cytotoxicity and DNA damage, whereas overexpression of DNA repair in similar cells is protective. 4. MAM alters gene expression in SY5Y human neuroblastoma cells and, in the presence of DNA damage and reduced DNA repair, enhances glutamate-modulated expression of tau mRNA in rat primary neurons; the corresponding protein (TAU) is elevated in ALS/PDC and Alzheimer's disease. These findings support a direct relationship between MAM-induced DNA damage and neurotoxicity and suggest the genotoxin may operate in a similar manner in vivo. More broadly, a combination of genotoxin-induced DNA damage (via exogenous and/or endogenous agents) and disturbed DNA repair may be important contributing factors in the slow and progressive degeneration of neurons that is characteristic of sporadic neurodegenerative disease. Preliminary studies demonstrate that DNA repair is reduced in the brain of subjects with western Pacific ALS/PDC, ALS, and Alzheimer's disease, which would increase the susceptibility of brain tissue to DNA damage by endogenous/exogenous genotoxins. Interindividual differences in the extent of prior exposure to DNA-damaging agents and/or the efficiency of its repair might produce population variety in the rate of damage accumulation and explain the susceptibility of certain individuals to sporadic neurodegenerative disease. Studies are underway using DNA-repair proficient and deficient neuronal cell cultures and mutant mice to explore gene-environment interplay with respect to MAM treatment, DNA damage, and DNA repair, and the age-related appearance of neurobehavioral and neuropathological compromise.
...
PMID:Damage and repair of nerve cell DNA in toxic stress. 1046 42

(-)-Deprenyl, used for the treatment of Parkinson's disease, was reported to possess neurorescuing/antiapoptotic effects independent of its MAO-B inhibiting properties. It is metabolized to (-)-desmethyldeprenyl, which seems to be the active principle, and further to (-)-amphetamine and (-)-methamphetamine, which antagonize its rescuing effects. These complications may explain the limited neurorescuing potential of (-)-deprenyl observed clinically. CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine), structurally related to (-)-deprenyl, exhibits virtually no MAO-B nor MAO-A inhibiting properties and is not metabolized to amphetamines. It was shown to bind to glyceraldehyde-3-phosphate dehydrogenase, a glycolytic enzyme with multiple other functions including an involvement in apoptosis, and shows neurorescuing properties qualitatively similar to, but about 100-fold more potent than those of (-)-deprenyl in several in vitro and in vivo paradigms. In concentrations ranging from 10(-13)-10(-5) M, it rescues partially differentiated PC12 cells from apoptosis induced by trophic withdrawal, cerebellar granule cells from apoptosis induced by cytosine arabinoside, rat embryonic mesencephalic dopaminergic cells from death caused by MPP+, and PAJU human neuroblastoma cells from death caused by rotenone. However, it did not affect apoptosis elicited by a variety of agents in rapidly proliferating cells from thymus or skin or in liver or kidney cells. In vivo, it rescued facial motor neuron cell bodies in rat pups after axotomy, rat hippocampal CA1 neurons after transient ischemia/hypoxia, and mouse nigral dopaminergic cell bodies from death induced by MPTP, in doses ranging between 0.0003 and 0.1 mg/kg p.o. or s.c., depending on the model. It also partially prevented the loss of tyrosine hydroxylase immunoreactivity in the substantia nigra of 6-OHDA-lesioned rats and improved motor function in these animals. Moreover, it prolonged the life-span of progressive motor neuronopathy (pmn) mice (a model for ALS), preserved their body weight and improved their motor performance. This was accompanied by a decreased loss of motor neurons and motor neuron fibers, and protection of mitochondria. The active concentration- or dose-ranges in the different in vitro and in vivo paradigms were remarkably similar. In several paradigms, bell-shaped dose-response curves were observed, the rescuing effect being lost above about 1 mg/kg, a fact that must be considered in clinical investigations.
...
PMID:Neurorescuing effects of the GAPDH ligand CGP 3466B. 1120 40

Human neuroblastoma SH-SY5Y cells transfected with either familial amyotrophic lateral sclerosis-typical G93A mutant or wild-type copper/zinc superoxide dismutase were compared to untransfected cells in term of glutamate transport. Vmax of glutamate uptake was reduced in mutant cells, with no change in Km. No difference in EAAT1, EAAT2 and EAAT3 glutamate transporter mRNAs and immunoreactive proteins was found, suggesting that one or more transporters are functionally inactivated, possibly due to increased oxidative stress induced by the G93A mutation. Mutant cells showed a marked sensitivity to oxidants, resulting in a more pronounced reduction of glutamate uptake. Short-term antioxidant treatment did not reverse the impairment of glutamate uptake in G93A cells. Interestlingly, N-acetylcysteine was partially effective in preventing glutamate uptake reduction due to exogenous oxidative insults. Since the inhibition of the EAAT2 transporter subtype had no effect on glutamate re-uptake in this model, our study suggests an impaired function of the EAAT1/3 transporter subtypes, possibly due to oxidative inactivation, in the presence of mutant copper/zinc superoxide dismutase. Therefore, this model might prove to be a valuable tool to study the effects of mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis on glutamate transport in neuronal cells, without the specific contribution of glial cells. These findings might lead to the identification of new therapeutic strategies aimed at preventing the damage associated with ALS.
...
PMID:Impairment of glutamate transport and increased vulnerability to oxidative stress in neuroblastoma SH-SY5Y cells expressing a Cu,Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis. 1567 Jun 39

BH3-only proteins couple diverse stress signals to the evolutionarily conserved mitochondrial apoptosis pathway. Previously, we reported that the activation of the BH3-only protein p53-up-regulated mediator of apoptosis (Puma) was necessary and sufficient for endoplasmic reticulum (ER) stress- and proteasome inhibition-induced apoptosis in neuroblastoma and other cancer cells. Defects in protein quality control have also been suggested to be a key event in ALS, a fatal neurodegenerative condition characterized by motoneuron degeneration. Using the SOD1(G93A) mouse model as well as human post mortem samples from ALS patients, we show evidence for increased ER stress and defects in protein degradation in motoneurons during disease progression. Before symptom onset, we detected a significant up-regulation of Puma in motoneurons of SOD1(G93A) mice. Genetic deletion of puma significantly improved motoneuron survival and delayed disease onset and motor dysfunction in SOD1(G93A) mice. However, it had no significant effect on lifespan, suggesting that other ER stress-related cell-death proteins or other factors, such as excitotoxicity, necrosis, or inflammatory injury, may contribute at later disease stages. Indeed, further experiments using cultured motoneurons revealed that genetic deletion of puma protected motoneurons against ER stress-induced apoptosis but showed no effect against excitotoxic injury. These findings demonstrate that a single BH3-only protein, the ER stress-associated protein Puma, plays an important role during the early stages of chronic neurodegeneration in vivo.
...
PMID:Deletion of the BH3-only protein puma protects motoneurons from ER stress-induced apoptosis and delays motoneuron loss in ALS mice. 1807 68

Mutations in the gene encoding cytosolic Cu,Zn-superoxide dismutase (SOD1) have been linked to familial amyotrophic lateral sclerosis (FALS). However the molecular mechanisms of motor neuron death are multi-factorial and remain unclear. Here we examined DNA damage, p53 activity and apoptosis in SH-SY5Y human neuroblastoma cells transfected to achieve low-level expression of either wild-type or mutant Gly(93)-->Ala (G93A) SOD1, typical of FALS. DNA damage was investigated by evaluating the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and DNA strand breaks. Significantly higher levels of DNA damage, increased p53 activity, and a greater percentage of apoptotic cells were observed in SH-SY5Y cells transfected with G93A SOD1 when compared to cells overexpressing wild-type SOD1 and untransfected cells. Western blot, FACS, and confocal microscopy analysis demonstrated that G93A SOD1 is present in the nucleus in association with DNA. Nuclear G93A SOD1 has identical superoxide dismutase activity but displays increased peroxidase activity when compared to wild-type SOD1. These results indicate that the G93A mutant SOD1 association with DNA might induce DNA damage and trigger the apoptotic response by activating p53. This toxic activity of mutant SOD1 in the nucleus may play an important role in the complex mechanisms associated with motor neuron death observed in ALS pathogenesis.
...
PMID:Increased SOD1 association with chromatin, DNA damage, p53 activation, and apoptosis in a cellular model of SOD1-linked ALS. 2009 85

Point mutations in the gene encoding copper-zinc superoxide dismutase (SOD1) impart a gain-of-function to this protein that underlies 20-25% of all familial amyotrophic lateral sclerosis (FALS) cases. However, the specific mechanism of mutant SOD1 toxicity has remained elusive. Using the complementary techniques of atomic force microscopy (AFM), electrophysiology, and cell and molecular biology, here we examine the structure and activity of A4VSOD1, a mutant SOD1. AFM of A4VSOD1 reconstituted in lipid membrane shows discrete tetrameric pore-like structure with outer and inner diameters 12.2 and 3.0nm respectively. Electrophysiological recordings show distinct ionic conductances across bilayer for A4VSOD1 and none for wildtype SOD1. Mouse neuroblastoma cells exposed to A4VSOD1 undergo membrane depolarization and increases in intracellular calcium. These results provide compelling new evidence that a mutant SOD1 is capable of disrupting cellular homeostasis via an unregulated ion channel mechanism. Such a "toxic channel" mechanism presents a new therapeutic direction for ALS research.
...
PMID:Mutant SOD1 forms ion channel: implications for ALS pathophysiology. 2193 Feb 7

Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS.
...
PMID:Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. 2377 55

Acetylation homeostasis is thought to play a role in amyotrophic lateral sclerosis, and treatment with inhibitors of histone deacetylases has been considered a potential and attractive therapeutic approach, despite the lack of a thorough study of this class of proteins. In this study, we have considerably extended previous knowledge on the expression of 13 histone deacetylases in tissues (spinal cord and muscle) from mice carrying two different ALS-linked SOD1 mutations (G93A-SOD1 and G86R-SOD1). We have then focused on class III histone deacetylases SIRT1 and SIRT2 that are considered relevant in neurodegenerative diseases. SIRT1 decreases in the spinal cord, but increases in muscle during the progression of the disease, and a similar expression pattern is observed in the corresponding cell models (neuroblastoma and myoblasts). SIRT2 mRNA expression increases in the spinal cord in both G93A-SOD1 and G86R-SOD1 mice but protein expression is substantially unchanged in all the models examined. At variance with other sirtuin modulators (sirtinol, AGK2 and SRT1720), the well-known SIRT1 inhibitor Ex527 has positive effects on survival of neuronal cells expressing mutant SOD1, but this effect is neither mediated by SIRT1 inhibition nor by SIRT2 inhibition. These data call for caution in proposing sirtuin modulation as a target for treatment.
...
PMID:Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological characterization of SIRT1 and SIRT2 pathways. 2494 89


1 2 Next >>

---