Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Huntington's disease (HD) is initiated by an abnormally expanded polyglutamine stretch in the huntingtin protein, conferring a novel property on the protein that leads to the loss of striatal neurons. Defects in mitochondrial function have been implicated in the pathogenesis of HD. Here, we have examined the hypothesis that the mutant huntingtin protein may directly interact with the mitochondrion and affect its function. In human neuroblastoma cells and clonal striatal cells established from HdhQ7 (wild-type) and HdhQ111 (mutant) homozygote mouse knock-in embryos, huntingtin was present in a purified mitochondrial fraction. Subfractionation of the mitochondria and limited trypsin digestion of the organelle demonstrated that huntingtin was associated with the outer mitochondrial membrane. We further demonstrated that a recombinant truncated mutant huntingtin protein, but not a wild-type, directly induced mitochondrial permeability transition (MPT) pore opening in isolated mouse liver mitochondria, an effect that was prevented completely by cyclosporin A (CSA) and ATP. Importantly, the mutant huntingtin protein significantly decreased the Ca2+ threshold necessary to trigger MPT pore opening. We found a similar increased susceptibility to the calcium-induced MPT in liver mitochondria isolated from a knock-in HD mouse model. The mutant huntingtin protein-induced MPT pore opening was accompanied by a significant release of cytochrome c, an effect completely inhibited by CSA. These findings suggest that the development of specific MPT inhibitors may be an interesting therapeutic avenue to delay the onset of HD.
 ...
PMID:Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. 1516 34

EUK4010 has been identified to exhibit an inhibitory effect on beta-amyloid (Abeta)(1-42)-induced loss of neuronal cell viability. Further studies demonstrated that EUK4010 attenuated the Abeta(1-42)-induced degeneration in both cultured rat hippocampal neurons and human neuroblastoma cells, as demonstrated by typical morphological changes, cell viability and the chip-based flow cytometric assay. Gene expression analysis using DNA microarray showed that the senescence marker calcium-binding protein, regucalcin (Rgn), GABA-A receptor pi subunit (Gabrp), the huntingtin binding protein, optineurin (Optn) and a semaphorin family plexin A3 similar protein (Plex-similar) changed their expression levels significantly in cultured neurons after Abeta(1-42) treatment. In this report, we have undertaken a chemical genetic approach to study the molecular basis of Abeta(1-42) effects on the neuronal degeneration. Our results demonstrate that EUK4010 completely blocked the Abeta(1-42)-induced up-regulation of GABA-A receptor pi subunit and the semaphorin family plexin A3 similar protein, and partially attenuated the down-regulation of senescence marker calcium-binding protein, regucalcin. These observations suggest that EUK4010 may prevent or reduce the Abeta toxicity by regulating the expression of genes involved in the Abeta induced neuronal degeneration. These genes may represent a promising target for the therapeutic drug development for Alzheimer's disease (AD) and other neurological disorders. Furthermore, EUK4010 and its analogues could potentially be developed as neuronal protective agents for the treatment of these diseases.
 ...
PMID:Protective effects of EUK4010 on beta-amyloid(1-42) induced degeneration of neuronal cells. 1693 Apr 28

Huntington disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG trinucleotide repeat in the first exon of the HD gene, which results in a toxic polyglutamine stretch within huntingtin, the protein it encodes. Understanding the normal function of this essential protein is vital to understanding the root of the disease, yet despite more than a decade of investigation, its role in the cell remains elusive. Identifying the subcellular localization of huntingtin and understanding its effects on global gene expression are critical to this endeavor. While most reports agree that huntingtin is predominantly a cytoplasmic protein, conflicting distribution patterns have been demonstrated at the subcellular level. Here, we examine wild-type huntingtin's localization in cultured cells by expressing the full-length human protein tagged with enhanced green fluorescent protein (EGFP) within its unspliced genomic context. In fibrosarcoma and neuroblastoma cells, huntingtin shows discrete punctate, perinuclear localization overlapping largely with the trans-Golgi and cytoplasmic clathrin-coated vesicles, implicating huntingtin in vesicle trafficking. To determine whether huntingtin is involved in trafficking a specific subset of proteins, we measured changes in global transcription levels in embryonic stem cells and neurons lacking huntingtin. Huntingtin null neurons exhibit a significant reduction in transcripts encoding proteins destined for the extracellular space, many of which are components of the extracellular matrix or involved in cellular adhesion, receptor binding and hormone activity. Together, these findings support a role for huntingtin in the intracellular trafficking of proteins required for the construction of the extracellular matrix.
 ...
PMID:Wild-type huntingtin participates in protein trafficking between the Golgi and the extracellular space. 1718 90

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by abnormal CAG repeat expansion in the IT15 gene encoding huntingtin protein (htt). Mutated htt is predicted to acquire toxic properties in specific brain regions. For instance, striatal neurons expressing dopamine receptors predominantly degenerate in HD patients. Although the basis of this specific vulnerability remains unclear, a great deal of evidence has documented the ability of the dopamine system to modulate the toxicity of expanded htt. To investigate the relationship between dopamine receptors and expanded htt, we transfected enhanced green fluorescent proteins (EGFP) tagged to normal (25 CAG) or mutant (103 CAG) htt in SK-N-MC neuroblastoma cells that endogenously express D1 receptors. Forming nuclear and cytoplasmic aggregates, mutant htt-EGFP was toxic to cells beyond 24 h post-transfection. Remarkably, low doses of a selective D1 receptors agonist or forskolin, an activator of adenylate cyclase, accelerated the formation of mutant htt nuclear aggregates, whereas the number of cytoplasmic aggregates was decreased. These effects were associated with a minor increase in cell death. Understanding the functional bases of these effects may further elucidate the role of dopamine receptors signaling in the complex pathophysiology of HD.
 ...
PMID:Dopamine D1 receptor-mediated aggregation of N-terminal fragments of mutant huntingtin and cell death in a neuroblastoma cell line. 1840 26

Huntington's disease (HD) is an autosomal dominant inheritable neurodegenerative disorder caused by expansion of a polyglutamine repeat in the amino-terminal region of huntingtin. Polyglutamine expansion causes mutant huntingtin to aggregate and accumulate in the nuclei and cytoplasm of neurons. The aggregated amino-terminal fragments of mutant huntingtin are toxic to neuronal cells and may be involved in the neurodegeneration in HD patient brains. Although nuclear mutant huntingtin has been found to affect gene expression, the effect of cytoplasmic mutant huntingtin remains to be investigated. We established stably transfected mouse neuroblastoma (N2a) cells that express soluble amino-terminal fragments of huntingtin containing 20 (20Q) or 150 (150Q) glutamine repeats. In these stable cell lines, both 20Q and 150Q are diffusely distributed in the cytoplasm without aggregate formation. However, the stable 150Q cells are deficient in neurite outgrowth. Compared with wild-type N2a cells and cells stably expressing 20Q, stable 150Q cells also have decreased viability and are more susceptible to apoptotic stimulation. These findings suggest that the cytoplasmic soluble mutant huntingtin is also toxic to cells.
 ...
PMID:Inhibition of neurite outgrowth and promotion of cell death by cytoplasmic soluble mutant huntingtin stably transfected in mouse neuroblastoma cells. 1865 14

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a poly-glutamine expansion in huntingtin, the protein encoded by the HD gene. PolyQ-expanded huntingtin is toxic to neurons, especially the medium spiny neurons of the striatum. At the same time, wild-type huntingtin has important - indeed essential - protective functions. Any effective molecular therapy must preserve the expression of wild-type huntingtin, while silencing the mutant allele. We hypothesized that an appropriate siRNA molecule would display the requisite specificity and efficacy. As RNA interference is incapable of distinguishing among alleles with varying numbers of CAG (glutamine) codons, another strategy is needed. We used HD fibroblasts in which the pathogenic mutation is linked to a polymorphic site: the Delta2642 deletion of one of four tandem GAG triplets. We silenced expression of the harmful Delta2642-marked polyQ-expanded huntingtin without compromising synthesis of its wild-type counterpart. Following this success in HD fibroblasts, we obtained similar results with neuroblastoma cells expressing both wild-type and mutant HD genes. As opposed to the effect of depleting wild-type huntingtin, specifically silencing the mutant species actually lowered caspase-3 activation and protected HD cells under stress conditions. These findings have therapeutic implications not only for HD, but also for other autosomal dominant diseases. This approach has great promise: it may lead to personalized genetic therapy, a holy grail in contemporary medicine.
 ...
PMID:Allele-specific silencing of mutant Huntington's disease gene. 1909 60

Huntington's disease is a hereditary neurodegenerative disorder caused by an aberrant polyglutamine expansion in the amino terminus of the huntingtin protein. The resultant mutant huntingtin form aggregates in neurons and causes neuronal dysfunction and degeneration in many ways including transcriptional dysregulation. Here, we report that the expression of mutant huntingtin in the mouse neuroblastoma cell results in massive transcriptional induction of several chemokines including monocyte chemoattractant protein-1 (MCP-1) and murine chemokine (KC). The mutant huntingtin expressing cells also exhibit proteasomal dysfunction and down-regulation of NF-kappaB activity in a time-dependent manner and both these phenomena regulate the expression of MCP-1 and KC. The expression of MCP-1 and KC are increased in the mutant huntingtin expressing cells in response to mild proteasome inhibition. However, the expression of MCP-1 and KC and proteasome activity are not altered and inflammation is rarely observed in the brain of 12-week-old Huntington's disease transgenic mice in comparison with their age-matched controls. Our result suggests that the mutant huntingtin-induced proteasomal dysfunction can up-regulate the expression of MCP-1 and KC in the neuronal cells and therefore might trigger the inflammation process.
 ...
PMID:Induction of chemokines, MCP-1, and KC in the mutant huntingtin expressing neuronal cells because of proteasomal dysfunction. 1918 96

Prions are self-propagating infectious protein aggregates of mammals and fungi. The exact mechanism of prion formation is poorly understood. In a recent study, a comparative analysis of the aggregation propensities of chimeric proteins derived from the yeast Sup35p and mouse PrP prion proteins was performed in neuroblastoma cells. The cytosolic expression of the Sup35p domains NM, PrP and fusion proteins thereof revealed that the carboxyterminal domain of PrP (PrP90-230) mediated aggregate formation, while Sup35p N and M domains modulated aggregate size and frequency when fused to the globular domain of PrP. Here we further present co-aggregation studies of chimeric proteins with cytosolic PrP or a huntingtin fragment with an extended polyglutamine tract. Our studies demonstrate that cross-seeding by heterologous proteins requires sequence similarity with the aggregated protein domain. Taken together, these results demonstrate that nucleation and seeding of prion protein aggregates is strongly influenced by dynamic interactions between the aggregate core forming domain and its flanking regions.
 ...
PMID:Dynamic interactions of Sup35p and PrP prion protein domains modulate aggregate nucleation and seeding. 1919 20

Huntington's disease (HD) is a neurodegenerative disease caused by mutant huntingtin protein containing an expanded polyglutamine tract, which may cause abnormal protein-protein interactions such as increased association with calmodulin (CaM). We previously demonstrated in HEK293 cells that a peptide containing amino acids 76-121 of CaM (CaM-peptide) interrupted the interaction between CaM and mutant huntingtin, reduced mutant huntingtin-induced cytotoxicity and reduced transglutaminase (TG)-modified mutant huntingtin. We now report that adeno-associated virus (AAV)-mediated expression of CaM-peptide in differentiated neuroblastoma SH-SY5Y cells, stably expressing an N-terminal fragment of huntingtin containing 148 glutamine repeats, significantly decreases the amount of TG-modified huntingtin and attenuates cytotoxicity. Importantly, the effect of the CaM-peptide shows selectivity, such that total TG activity is not significantly altered by expression of CaM-peptide nor is the activity of another CaM-dependent enzyme, CaM kinase II. In vitro, recombinant exon 1 of huntingtin with 44 glutamines (htt-exon1-44Q) binds to CaM-agarose; the addition of 10 microM of CaM-peptide significantly decreases the interaction of htt-exon1-44Q and CaM but not the binding between CaM and calcineurin, another CaM-binding protein. These data support the hypothesis that CaM regulates TG-catalyzed modifications of mutant huntingtin and that specific and selective disruption of the CaM-huntingtin interaction is potentially a new target for therapeutic intervention in HD.
 ...
PMID:Neuroprotective effects of calmodulin peptide 76-121aa: disruption of calmodulin binding to mutant huntingtin. 1933 77

Proteins prone to misfolding form large macroscopic deposits in many neurodegenerative diseases. Yet the in situ aggregation kinetics remains poorly understood because of an inability to demarcate precursor oligomers from monomers. We developed a strategy for mapping the localization of soluble oligomers and monomers directly in live cells. Sensors for mutant huntingtin, which forms aggregates in Huntington's disease, were made by introducing a tetracysteine motif into huntingtin that becomes occluded from binding biarsenical fluorophores in oligomers, but not monomers. Up to 70% of the diffusely distributed huntingtin molecules appeared as submicroscopic oligomers in individual neuroblastoma cells expressing mutant huntingtin. We anticipate the sensors to enable insight into cellular mechanisms mediated by oligomers and monomers and for the approach to be adaptable more generally in the study of protein self-association.
 ...
PMID:Conformation sensors that distinguish monomeric proteins from oligomers in live cells. 2041 8


<< Previous 1 2 3 4 Next >>