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

The toxicity caused by the artemisinin derivative dihydroartemisinin in differentiated NB2a neuroblastoma cells was studied by transmission and scanning electron microscopy, Western blotting and immunocytochemistry. Western blotting with monoclonal antibodies failed to detect any specific changes in the cell cytoskeleton, nor were any changes detected by immunocytochemistry. This was consistent with electron microscopy of surviving cell neurites. Transmission electron microscopy revealed that dihydroartemisinin damaged NB2a cell mitochondrial cristae and endoplasmic reticulum. Scanning electron microscopy revealed that dihydroartemisinin depleted the filopodia-like processes projecting from the surface of the cell body and neurites. Some, or all, of these drug-induced changes in differentiating NB2a cells may have a role in the neurotoxicity of artemisinin derivatives.
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PMID:Morphological and immunocytochemical effects of dihydroartemisinin on differentiating NB2a neuroblastoma cells. 962 45

The sarco/endoplasmic reticulum Ca(2+)-transport ATPase (SERCA2) pre-mRNA is alternatively processed in a tissue-specific manner. At its 3' end, two 5' splice donor sites compete for the same 3' acceptor splice site (3'A). While the upstream 5' donor splice site (5'D1) is used in muscle cells giving rise to the class 1 mRNA, the downstream one (5'D2) is exclusively used in neuronal cells generating the class 4 mRNA. Using a neuroblastoma cell line and a minigene containing the 3' end of the SERCA2 gene, we have investigated the regulation of the neuronal-type of splicing. We have shown that a strong 3'A is required for splicing because exchanging it for a weaker one abolishes splicing. A second region spanning the entire exon 25 downstream of the 3'A is also necessary for the repression of the muscle-specific splicing in neuronal cells. In addition the tissue-specific (muscle/neuron) selection of the appropriate 5' donor splice site seems to be determined by at least two distinct but adjacent negative cis-active elements located in the last 237 nt of the optional exon 24. The upstream negative element controls the neuronal splicing while the downstream one represses the muscle-specific splicing in neuronal cells. It is suggested that the cis-active elements in the gene transcript are the target of trans-acting factors that are responsible for the repression of neuronal- or muscle-specific splicing in a tissue-specific manner.
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PMID:Regulation of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) 2 gene transcript in neuronal cells. 964 64

Mutations in the presenilin genes PS1 and PS2 cause the most common form of early-onset familial Alzheimer's disease. The influence of PS1 mutations on the generation of endogenous intracellular amyloid beta-protein (A beta) species was assessed using a highly sensitive immunoblotting technique with inducible mouse neuroblastoma (Neuro 2a) cell lines expressing the human wild-type (wt) or mutated PS1 (M146L or delta exon 10). The induction of mutated PS1 increased the intracellular levels of two distinct A beta species ending at residue 42 that were likely to be A beta1-42 and its N-terminally truncated variant(s) A beta x-42. The induction of mutated PS1 resulted in a higher level of intracellular A beta1-42 than of intracellular A beta x-42, whereas extracellular levels of A beta1-42 and A beta x-42 were increased proportionally. In addition, the intracellular generation of these A beta42 species in wt and mutated PS1-induced cells was completely blocked by brefeldin A, whereas it exhibited differential sensitivities to monensin: the increased accumulation of intracellular A beta x-42 versus inhibition of intracellular A beta1-42 generation. These data strongly suggest that A beta x-42 is generated in a proximal Golgi, whereas A beta1-42 is generated in a distal Golgi and/or a post-Golgi compartment. Thus, it appears that PS1 mutations enhance the degree of 42-specific gamma-secretase cleavage that occurs in the normal beta-amyloid precursor protein processing pathway (a) in the endoplasmic reticulum or the early Golgi apparatus prior to beta-secretase cleavage or (b) in the distinct sites where A beta x-42 and A beta1-42 are generated.
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PMID:Presenilin 1 mutations linked to familial Alzheimer's disease increase the intracellular levels of amyloid beta-protein 1-42 and its N-terminally truncated variant(s) which are generated at distinct sites. 975 Nov 87

The neuronal microtubule-associated protein tau plays an important role in establishing cell polarity by stabilizing axonal microtubules that serve as tracks for motor-protein-driven transport processes. To investigate the role of tau in intracellular transport, we studied the effects of tau expression in stably transfected CHO cells and differentiated neuroblastoma N2a cells. Tau causes a change in cell shape, retards cell growth, and dramatically alters the distribution of various organelles, known to be transported via microtubule-dependent motor proteins. Mitochondria fail to be transported to peripheral cell compartments and cluster in the vicinity of the microtubule-organizing center. The endoplasmic reticulum becomes less dense and no longer extends to the cell periphery. In differentiated N2a cells, the overexpression of tau leads to the disappearance of mitochondria from the neurites. These effects are caused by tau's binding to microtubules and slowing down intracellular transport by preferential impairment of plus-end-directed transport mediated by kinesin-like motor proteins. Since in Alzheimer's disease tau protein is elevated and mislocalized, these observations point to a possible cause for the gradual degeneration of neurons.
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PMID:Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. 981 97

The excessive generation and accumulation of 40- and 42-aa beta-amyloid peptides (Abeta40/Abeta42) in selectively vulnerable brain regions is a major neuropathological feature of Alzheimer's disease. Abeta, derived by proteolytic cleavage from the beta-amyloid precursor protein (betaAPP), is normally secreted. However, recent evidence suggests that significant levels of Abeta also may remain inside cells. Here, we have investigated the subcellular compartments within which distinct amyloid species are generated and the compartments from which they are secreted. Three experimental approaches were used: (i) immunofluorescence performed in intact cortical neurons; (ii) sucrose gradient fractionation performed with mouse neuroblastoma cells stably expressing wild-type betaAPP695 (N2a695); and (iii) cell-free reconstitution of Abeta generation and trafficking from N2a695 cells. These studies demonstrate that: (i) Abeta40 (Abeta1-40 plus Abetax-40, where x is an NH2-terminal truncation) is generated exclusively within the trans-Golgi Network (TGN) and packaged into post-TGN secretory vesicles; (ii) Abetax-42 is made and retained within the endoplasmic reticulum in an insoluble state; (iii) Abeta42 (Abeta1-42 plus Abetax-42) is made in the TGN and packaged into secretory vesicles; and (iv) the amyloid peptides formed in the TGN consist of two pools (a soluble population extractable with detergents and a detergent-insoluble form). The identification of the organelles in which distinct forms of Abeta are generated and from which they are secreted should facilitate the identification of the proteolytic enzymes responsible for their formation.
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PMID:Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides. 989 4

The known neurotoxicity of high doses of arteether and dihydroartemisinin in experimental animals has led to the need for a rapid screening method to predict the potential neurotoxicity of newly developed artemisinin-related antimalarial drugs. We have studied the effects of a range of these compounds on the neurite outgrowth of differentiating NB2a neuroblastoma cells in vitro, an assay that shows a correlation with neurotoxicity in vivo for a range of neurotoxic agents. In this assay, dihydroartemisinin is significantly more toxic than artemether or arteether. In the presence of liver metabolising enzymes, in vitro neurotoxicity of artemether and arteether is markedly increased. Differentiated neuronal cells are more sensitive than differentiated glial cells. Electron microscopy confirms that the targets in the neuronal cell for dihydroartemisinin are mitochondrial membranes and endoplasmic reticulum. The technique forms a valuable component of a range of appropriate neurotoxicity screening tests that should continue to be applied to newly developed antimalarials of this type.
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PMID:In vitro neurotoxicity of artemisinin derivatives. 1021 94

Diisopropyl phosphorofluoridate (DFP) is an organophosphorus ester, and a single injection of this compound (1.7 mg/kg, s.c.) produces delayed neurotoxicity (OPIDN) in hens in 7-14 days. Clinically, the disease is marked by hindlimb ataxia followed by paralysis after some time. A characteristic feature of this neuropathy is axonal swelling in the initial stages and comparative dissolution of the accumulated material and degeneration of distal axons with disease progression. Axonal swelling consists of aggregated neurofilaments, microtubules, and proliferated smooth endoplasmic reticulum. We studied expression of neurofilament (NF) mRNAs in brain regions and spinal cord to elucidate their role in OPIDN. There was a 50-200% increase in NF transcripts in 24 hr after DFP administration. The NF-L mRNA level started falling after 1-5 days and came down to control level in susceptible brain regions (i.e. cerebellum and brainstem) and spinal cord, but not in cerebral cortex, which does not show degeneration of axons in OPIDN. Cerebral cortex exhibited elevated levels of both NF-L and NF-M transcripts in DFP-treated hens throughout the period of observation. The induction of NF messages is consistent with the previously reported effect on extension of neurites of human neuroblastoma cells in culture. The transient increase in NF messages in susceptible tissues either may be responsible for the delayed degeneration of axons in OPIDN or is the result of interruption of regulatory signal due to progressive degeneration of axons.
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PMID:Enhanced mRNA expression of neurofilament subunits in the brain and spinal cord of diisopropyl phosphorofluoridate-treated hens. 1023 Jul 68

6-diazo-5-oxo-L-norleucine (DON) exerts a growth inhibitory effect selectively on the neuroendocrine tumour cell line BON and is proposed as an antitumour drug. The mechanism behind this has not yet been clarified. In the present study, transmission electron microscopy was used for the assessment of changes in cellular organelles. Furthermore, the methylthiazolyldiphenyl tetrazolium (MTT) assay for mitochondrial enzymatic activity, a fluorescent marker (rhodamine 123) for mitochondrial integrity and [2-(11)C]-acetyl-carnitine which is a substrate of the tricarboxylic acid cycle of mitochondria were employed. The studies were performed in parallel in BON and in a neuroblastoma cell line LAN, with the cells grown as monolayers or as multicellular aggregates. Severe morphological changes of intracellular organelles were observed in BON aggregates treated with low-doses of DON. Especially striking was the disruption of mitochondrial internal membrane structures. Other features included the swelling of endoplasmic reticulum, autophagocytosis of secretory granules and nuclear condensation (apoptosis). In LAN cells, no ultrastructural changes were seen after DON treatment. The MTT assay indicated inhibition of mitochondrial enzymatic activity in BON cells but not in LAN cells after 5 h treatment with DON. The mitochondrial damage was also demonstrated as a reduced metabolism of [2-(11)C]-acetyl-carnitine. The observations revealed mitochondrial damage by DON treatment and suggest that the mitochondria might be a primary target for the antitumour effect in neuroendocrine cells.
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PMID:A mechanism behind the antitumour effect of 6-diazo-5-oxo-L-norleucine (DON): disruption of mitochondria. 1053 63

Conformational conversion of the cellular PrPC protein to PrPSc is a central aspect of the prion diseases, but how PrP initially converts to this conformation remains a mystery. Here we show that PrP expressed in the yeast cytoplasm, instead of the endoplasmic reticulum, acquires the characteristics of PrPSc, namely detergent insolubility and a distinct pattern of protease resistance. Neuroblastoma cells cultured under reducing, glycosylation-inhibiting conditions produce PrP with the same characteristics. We therefore describe what is, to our knowledge, the first conversion of full-length PrP in a heterologous system, show the importance of reducing and deglycosylation conditions in PrP conformational transitions, and suggest a model for initiating events in sporadic and inherited prion diseases.
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PMID:De novo generation of a PrPSc-like conformation in living cells. 1055 63

Although calreticulin (Crt) is primarily localized to the endoplasmic reticulum (ER), our results using biotinylation and immunocytochemical methods indicate that a small but significant amount of Crt is present and forms large patches on the surface of NG108-15 cells (a mouse neuroblastoma-rat glioma hybrid cell line). (35)S-labelled Crt molecules begin to reach the cell surface after only 10 min of labelling and disappear slowly from the cell surface. After 4 hr of labelling, approximately half of the newly synthesized Crt molecules are on the cell surface. We believe that some Crt molecules may escape from the KDEL receptor-mediated salvage pathway as they are synthesized and proceed through the secretory pathway to the cell surface. Immunoprecipitation from the culture medium shows that Crt is not released from the cell surface to the medium, suggesting tight binding to surface molecules. NH(4)Cl can block the degradation of Crt; therefore, Crt is presumably degraded in the lysosome pathway. However, blockage of the disappearance of surface Crt is less efficient than that of internal Crt. This suggests that the disappearance of Crt from the cell surface may not be due solely to its degradation, but may reflect transport into another cell compartment such as the ER.
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PMID:Calreticulin is transported to the surface of NG108-15 cells where it forms surface patches and is partially degraded in an acidic compartment. 1056 93


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