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PubMed1994

The regulation of membrane 125I- and 86Rb+ permeability in a virally transformed cell line (NCL-SG3) derived from the human sweat gland epithelium.

We have explored the factors that may regulate membrane permeability in a cell line (NCL-SG3) derived from the human sweat gland epithelium. Ionomycin increased the rate of 125I-efflux from preloaded cells and this action appeared to be due to an increase in intracellular free calcium ([Ca2+]i). The ionomycin-evoked increase in 125I- efflux was reduced in cells that were exposed either to barium or to valinomycin in the presence of a high concentration of external potassium. It thus appears that a fraction of the ionomycin-evoked increase in 125I- efflux is due to the activation of potassium channels and experiments using 86Rb+ also suggested that ionomycin increased the rate of potassium efflux, an effect which was totally abolished by barium. Blockade of Na(+)-K(+)-2Cl- cotransport and of Cl- -HCO3- exchange reduced the basal rate of 125I- efflux and the ionomycin-evoked increase in 125I-efflux from control cells and from cells depolarized by valinomycin. These transport systems thus contribute to anion efflux, although [Ca2+]i-dependent chloride channels also appear to be present. Acetylcholine increases [Ca2+]i in the secretory cells of human sweat glands, but this neurotransmitter did not increase [Ca2+]i in NCL-SG3 cells and so membrane permeability was not under cholinergic control. Adrenaline did not increase [Ca2+]i, but this hormone did evoke cyclic-3',5'-adenosine monophosphate (cyclic AMP) production. However, membrane permeability was not under adrenergic control, as the cells did not appear to express functional, cyclic AMP-dependent anion channels. This may be because they were not fully differentiated under the culture conditions. ATP consistently evoked a dose-dependent increase in anion efflux that appeared to be mediated by [Ca2+]i. The increase in [Ca2+]i was initiated by the release of calcium from a limited internal store and was subsequently sustained by calcium influx. UTP and ADP also increased [Ca2+]i, whereas adenosine, AMP and alpha,beta-methylene ATP were without effect. These data thus suggest that a subclass of type 2 purine receptor, which is functionally coupled to phosphoinositidase C, is present in these cells.

Calcium↗
PubMed1995

Decline in glucose metabolism in the brain in neuronal ceroid lipofuscinosis (NCL) in English setter--evidence by positron emission tomography (PET).

Positron emission tomography scans were performed on brains of homozygous and heterozygous English setters with neuronal ceroid-lipofuscinosis (NCL) from 13 months of age to 24-25 months of age for homozygous dogs and to 38 months for heterozygous dogs, respectively. After iv injection of 18F-fluorodeoxyglucose (FDG), 7 coronal brain scans as well as sequential arterial blood samplings were performed for 45 min under pentobarbital anesthesia. From these data, three different functional images (DAR (standardized uptake value), FDG uptake (fractional uptake) and glucose uptake) were reconstructed and quantitatively analysed. In the age range from 13 to 15 months, glucose images were comparable for both homozygous and heterozygous dogs, so that no differentiation was possible between healthy and diseased dogs on the basis of PET findings. Between 18 and 24 months of age, a drastic decline in glucose metabolism was observed in homozygous dogs, while the decline in glucose utilization was very mild in this period for heterozygous dogs. Furthermore, in PET scans, cerebral atrophy and ventricular enlargement were clearly shown in homozygous dogs. Consequently at the age from 20 to 24 months, a clear differential diagnosis between healthy (heterozygous) and diseased (homozygous) dogs became possible even if the clinical symptoms were still not clear in the latter. We conclude that the biochemical alterations in the brain in canine NCL occurs and progresses very rapidly in the last quarter of their lives.

Aging↗
PubMedDate not supplied

Axonal enlargements (meganeurites) in neuronal ceroid lipofuscinosis (NCL).

Meganeurites have been described by light and electron microscopy in several neuronal lipid storage diseases. In neuronal ceroid lipofuscinosis (NCL), they appear to be less frequent. We present the first combined Golgi-electron microscopy study of a patient with NCL, which shows that the axons from neurons with meganeurites arise from their distal poles. Our results reinforce the assumption that neuronal malfunction in this disorder, as in other neuronal storage diseases, is also due to the presence of such meganeurites in the area of the axon hillock-initial axon segment.

Axons↗
PubMed1993

Genetic heterogeneity in neuronal ceroid lipofuscinosis (NCL): evidence that the late-infantile subtype (Jansky-Bielschowsky disease; CLN2) is not an allelic form of the juvenile or infantile subtypes.

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in neurons and other cell types. Inheritance is autosomal recessive. Three main childhood subtypes are recognized: infantile (Haltia-Santavuori disease; MIM 256743), late infantile (Jansky-Bielschowsky disease; MIM 204500), and juvenile (Spielmeyer-Sjögren-Vogt, or Batten, disease; MIM 204200). The gene loci for the juvenile (CLN3) and infantile (CLN1) types have been mapped to human chromosomes 16p and 1p, respectively, by linkage analysis. Linkage analysis of 25 families segregating for late-infantile NCL has excluded these regions as the site of this disease locus (CLN2). The three childhood subtypes of NCL therefore arise from mutations at distinct loci.

Alleles↗
PubMed2006

The chemical synthesis of the GstI protein by NCL on a X-Met site.

The small GstI protein (63 amino acids) of Rhizobium leguminosarum is the endogenous inhibitor of the glnII (glutamine synthetase II) gene expression. It has been suggested that GstI has a predominantly beta-structure and mediates the block of translation and stabilization of glnII mRNA through direct binding to its 5' untranslated region. Because of the unavailability of adequate amounts of purified recombinant protein, the mechanism as well as the protein tridimensional structure remain very poorly understood. To obtain the full-length protein, we have undertaken the chemical synthesis of the protein by different approaches. In a first attempt, the stepwise synthesis was unsuccessful, with strong aggregation experienced on the N-terminal side, after residue 44 from the C-terminus. In a second approach, we set up the conditions to carry out a native chemical ligation (NCL). Albeit the protein contains two Cysteine residues, located at positions 40 and 47, to minimize the size of the N-terminal segment to be synthesized, we have devised an alternative strategy of ligation on Met32, utilizing homoCys as the ligating moiety and then alkylating the resulting polypeptide with methyl iodide. New conditions to quantitatively methylate thiol groups in complex polypeptides have been conceived, obtaining the protein in very good yields and purity. A CD spectroscopy investigation has revealed that the protein does not adopt canonical secondary structures but is very rich in beta-structure (approximately 60%), in agreement with a previous study carried out on samples obtained by recombinant methods.

Amino Acid Sequence↗
PubMed1987

NCL-5D3: a new monoclonal antibody recognizing low molecular weight cytokeratins effective for immunohistochemistry using fixed paraffin-embedded tissue.

Production of a new monoclonal antibody designated NCL-5D3 is described. The antibody recognizes several low molecular weight cytokeratins, in particular cytokeratin Moll number 8 as determined by immunoblotting studies, and is highly effective for immunocytochemistry using routinely processed paraffin-embedded material. Staining is enhanced by prior treatment of the sections with trypsin. Assessment using a wide variety of normal and neoplastic tissue indicates reactivity with all tissues of simple or glandular epithelial origin, and in addition with many squamous carcinomas. Thus the antibody should prove of value in diagnostic histopathology.

Antibodies, Monoclonal↗
PubMed1999

The European Concerted Action NCL Clinical Case Registry.

A European NCL Clinical Case Registry has been set up in London, as part of a European Union-funded Concerted Action project. Concerted Action participants provide written information about children which is then anonymized and entered on the Registry. Contributors are able to request information contained within the Registry for the purpose of epidemiological, molecular, diagnostic, or therapeutic research. Up to May 1998, 60 cases were entered on the Registry.

Europe↗
PubMed2000

Northern epilepsy, a new member of the NCL family.

Northern epilepsy, or progressive epilepsy with mental retardation (EPMR), is an autosomal recessive disorder characterized by normal early development, onset of generalized tonic-clonic seizures between the ages of 5 and 10 years, and subsequent progressive mental retardation. The seizures increase in frequency until puberty after which the epileptic activity starts to decline. Mental retardation begins 2-5 years after the onset of seizures and continues through adulthood. Neuropathological findings have shown that EPMR is a new member (CLN8) of the neuronal ceroid lipofuscinosis (NCL) group of neurodegenerative disorders. The CLN8 gene was identified recently. It encodes a 286 amino acid putative transmembrane protein with no homology to previously known proteins. Subsequently, the homologous mouse gene (Cln8) was sequenced and localized to the region of the mouse genome linked to motor neuron degeneration, mouse mnd. Mnd is a naturally occurring mouse mutant with intracellular autofluorescent inclusions similar to those seen in human CLN8. A mutation in mnd mouse DNA was identified, indicating that mnd is a murine model for CLN8.

Animals↗
PubMed2005

NCL-CD30 staining of epithelial cells in the basal germinative layer of the epidermis and epithelial buds during foetal skin development.

The fact that the CD30 molecule can mediate signals for cell proliferation or apoptosis prompted us to perform a systematic investigation of CD30 antigen expression in embryonal tissues during proliferation and differentiation stages. We first targeted the foetal human intestinal cryptae cells with positive results. The epidermis is a dynamic epithelium that is constantly renewed throughout life. The basal layer, attached to the basement membrane, contains the dividing cells of the skin and as cells move up from this layer they undergo differentiation, ending in the formation of a terminally differentiated anucleate cell called squame. It is intriguing to find out if cells in the basal layer can express the CD30 antigen. We investigated the immunohistochemical expression of CD30 antigen in 15 paraffin-embedded tissue samples representing epidermis and epidermal buds from foetuses after spontaneous abortion in the 8th, 10th and 12th weeks of gestation, respectively, using the monoclonal antibody NCL-CD30. A Northern blotting analysis was additionally performed. The results showed that: (1) the epithelial cells of the epidermis in the developing skin express the CD30 antigen; (2) CD30 expression in these epithelial cells is higher in cases of hormonal administration than in normal gestation; (3) a similar positive reaction involved the epidermal buds associated with the development of the skin appendages. Northern blots of tissue sections using a CD30 cDNA probe detected mRNAs of the same molecular mass and variety similarly to those in the positive control cell line HUT 102.

Antibodies, Monoclonal↗
PubMed1990

NCL-6-124I: a PET agent for the adrenal.

The radiopharmaceutical 6 beta-[124I]iodomethyl-19-nor-cholest-5(10)-en-3 beta-ol (NCL-6-124I) was synthesized. The product was less sensitive to autoradiolytic decomposition in chloroform, than when stored as an injectable solution at 5 degrees C.

Adosterol↗
PubMed1988

Purification and characterisation of glucose (xylose) isomerase from Chainia sp. (NCL 82-5-1).

Glucose (xylose) isomerase is an important enzyme in high fructose syrup industry. The enzyme generally occurs intracellularly and is specific for both glucose and xylose. A rare actinomycete Chainia sp. (NCL 82-5-1) produces extracellular specific glucose and xylose isomerases and an intracellular glucose (xylose) isomerase. The intracellular enzyme is isolated by cell autolysis and purified by preparative polyacrylamide gel electrophoresis. Its properties are studied and compared with those of extracellular specific xylose isomerase. The intracellular enzyme has a molecular weight of 1,58,000 daltons with four equal subunits of 40,700 daltons. The N-terminal amino acid sequence analysis shows Arg at the N-terminal. Diethylpyrocarbonate inhibited the enzyme and the inhibition kinetics study shows the presence of at least 2 essential His residues. The amino acid analysis shows the absence of Cys and a high proportion of hydrophobic and acidic amino acids.

Actinomyces↗
PubMed1997

The ovine model of neuronal ceroid lipofuscinosis (NCL): its contribution to understanding the pathogenesis of Batten disease.

Development of the ovine model of NCL has been pivotal to our present understanding of the ceroid lipofuscinoses. Analyses of isolated storage product have shown it to be composed of identifiable chemical species of which subunit c of mitochondrial ATP synthase is dominant (ca 50%). It is an extremely hydrophobic protein and failure to catabolise it may be associated with a propensity to form paracrystalline structures with lipids that cannot be degraded by the normal complement of lysosomal enzymes. However, the putative biochemical defect must be related to it and may reside within the mitochondria. Multiple copies of subunit c help form the transmembrane Fo complex which, with partially immobilised lipids, forms an Fo complex domain. This may need to be disassembled in an orderly fashion before proteolysis of subunit c can occur. It is postulated that the primary defect may involve disassembly of the Fo complex domain which may involve more than one step.

ATP Synthetase Complexes↗
PubMed2000

Phenotype-genotype correlation in eight patients with Finnish variant late infantile NCL (CLN5).

The authors analyzed the clinical phenotype, including MRI, of eight patients with Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCLFin; CLN5; MIM256731). Although the four known mutations, including one novel mutation identified in this study, have very different consequences for the predicted polypeptide, none of them results in an atypical phenotype, as has been reported in other forms of NCL. Thus, it seems likely that each mutation severely disturbs the normal function of the CLN5 protein.

Adolescent↗
PubMed1989

NCL-SG3: a human eccrine sweat gland cell line that retains the capacity for transepithelial ion transport.

An ion-transporting human epithelial cell line, NCL-SG3, has been established by simian virus 40 (SV40) infection of primary cultures from eccrine sweat glands. The line has been passaged 38 times (over 100 population doublings), has an aneuploid karyotype but has not undergone any 'crisis'. The cells have retained epithelial morphology and expression of cytokeratin, the intermediate filament characteristic of epithelial cells. Approximately 85% of the population shows at least weak co-expression of vimentin, an intermediate filament associated with mesenchymal and some other non-epithelial cell types in vivo. In addition, SV40 large T-antigen is present, in a predominantly nuclear localization. Electrically resistant cell sheets are formed on dialysis tubing and cellulose-ester permeable supports. Electrogenic ion transport can be stimulated by the beta-adrenergic agonist isoproterenol (10(-6) M) and by lysylbradykinin (10(-7) M) but not by the cholinergic agonist carbachol at 10(-6) M).

Biological Transport, Active↗
PubMed1976

The neurophysiological features of various diseases with NCL storage.

Combined EEG/ERG/VER studies were carried out on 47 children with verified neuronal storage of ceroid/lipofuscin-like material. The majority of patients fell into one of three main groups. Each group showed its own characteristic combination of neurophysiological features which were of diagnostic importance and closely parallel to the age of onset and the evolution of clinical symptoms characteristic to each group. These findings suggest that general terms such as "NCL" or "Batten's disease" imply a single disease process and are misleading.

Brain↗
PubMed2005

Prenatal diagnostic testing for infantile and late-infantile neuronal ceroid lipofusinoses (NCL) using allele specific primer extension (ASPE).

Infantile (INCL, NCL1) and late-infantile (LINCL, NCL2) neuronal ceroid lipofuscinoses have been found to result from genetic deficiency of genes CLN(1 ) and CLN(2), respectively. The application of molecular analyses can facilitate prenatal diagnosis for families affected by NCL1 or NCL2, in which the familial mutation(s) have been identified. Molecular testing with allele-specific primer extension and DNA sequencing was performed in nine pregnancies, four from two NCL1 families and five from five NCL2 families. Lysosomal enzyme activity assays were carried out as well.Four fetuses from three pregnancies in NCL1 families were found to be carriers for a mutation 451C-T in the CLN(1) gene and one was normal. Prenatal testing of three NCL2 families who carried mutation R208X in the CLN(2) gene showed that all fetuses were carriers. In NCL2 families who carried either mutation IVS5-1C or/and IVS5-1A two normal pregnancies were detected. Our studies indicate that DNA testing, which may provide definitive prenatal diagnosis for NCL, may be used in combination with lysosomal enzyme activity analyses.

Alleles↗
PubMed1994

Cloning of promoter-active DNA sequences from Chainia (NCL 82.5.1) in Escherichia coli.

The ability of Escherichia coli cells to recognise and use the regulatory signals of genes from Chainia (NCL 82-5-1) was determined in vivo using gene fusions. DNA fragments from Chainia were cloned in E. coli using the promoter probe plasmid pJAC4. Four of the randomly selected recombinants exhibited varying strengths of promoter activity as assessed by the concentration of ampicillin required to kill 50% of the colonies (LD50 values) and by beta-lactamase activity. The origin of the inserts was confirmed by colony hybridization of clones with labelled genomic DNA of Chainia. The beta-lactamase activity of recombinant colonies was substantially higher (> 10-fold) than that of colonies transformed with pJAC4 without any insert. The results show that a few Chainia DNA sequences are recognized by E. coli as transcription initiation signals for the expression of beta-lactamase gene, inspite of the high guanine/cytosine content of the Chainia genome.

Actinomycetales↗
PubMed1993

X-ray microanalysis of cAMP-induced ion transport in NCL-SG3 sweat gland cells.

cyclic AMP (cAMP)-induced ion transport in a human sweat gland cell line, NCL-SG3, was investigated by X-ray microanalysis. Stimulation with cAMP caused a decrease in cellular Cl and K content in cells grown on impermeable as well as permeable supports. In cells grown on plastic coverslips or Transwell inserts stimulation with cAMP caused a significant decrease of the Na concentration, but no significant effect on the intracellular Na was seen on cells grown on grids. cAMP had no significant effect on the intracellular Ca concentration.

Cell Line↗