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PubMed1989

Expression of pan-neuroendocrine proteins in 53 neuroblastic tumors. An immunohistochemical study with neuron-specific enolase, chromogranin, and synaptophysin.

The presence and distribution of pan-neuroendocrine markers such as neuron-specific enolase (NSE), chromogranin (CG), and synaptophysin (SYP) were investigated by immunohistochemistry in 53 cases of neuroblastic tumors, including three cases of ganglioneuromas, 17 ganglioneuroblastomas, and 33 neuroblastomas. In ganglioneuromas, all three markers were observed both in ganglion cells and in neurofibrils. All cases of ganglioneuroblastoma were positive for these markers, however, some variability of staining intensity was noted. Of the 33 cases of neuroblastomas, all were positive for NSE, 23 (70%) for CG, and 31 (94%) for SYP. Neuron-specific enolase was detected not only in the majority of the neuroblasts showing signs of differentiation, but also in some undifferentiated neuroblasts. Chromogranin was found mainly in differentiated neuroblasts with enlarged cytoplasm and nuclei, but was scarcely found in undifferentiated cells. Synaptophysin was detected in some undifferentiated neuroblasts, as well as in differentiated neuroblasts. Two cases without SYP-positive cells were also negative for CG. Our observations conclude that antibodies against NSE and SYP are helpful as a diagnostic aid for neuroblastic tumors.

Biomarkers, Tumor↗
PubMedDate not supplied

Regional cerebral blood flow and neuron-specific enolase in cerebrospinal fluid in children with acute lymphoblastic leukemia during induction treatment.

PURPOSE: To investigate possible side effects on the central nervous system from intrathecal methotrexate given during induction treatment for acute lymphoblastic leukemia in childhood. PATIENTS AND METHODS: Twenty-five children with acute lymphoblastic leukemia were examined by cerebral single photon emission computed tomography at the beginning of treatment (16 untreated, 9 during the first week) and after 4 weeks of treatment. Cerebrospinal fluid was sampled for analyses of neuron-specific enolase on four occasions in 54 patients. RESULTS: Regional cerebral blood flow became impaired during treatment in all patients. The single photon emission computed tomography score for nonhomogeneous perfusion increased from 6.4/50 to 16.6/50. Hypoperfusion was global without any clear preference for any lobe. The cerebellum was not affected. Neuron-specific enolase increased significantly during treatment, with a peak after 1 week, followed by a gradual decrease, but it was still significantly elevated after 4 weeks. CONCLUSIONS: Nonhomogeneous cerebral hypoperfusion was found in all patients during induction treatment, including repeated intrathecal administration of methotrexate, but before systemic high-dose methotrexate. Signs of neuronal injury, in the form of a moderate increase in neuron-specific enolase in the cerebrospinal fluid, were found early in the treatment. Follow-up is needed to evaluate the long-term impact of these findings.

Adolescent↗
PubMed2002

Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A.

We measured autoantibodies against nine different neuron-specific antigens and three cross-reactive peptides in the sera of autistic subjects and healthy controls by means of enzyme-linked immunosorbent assay (ELISA) testing. The antigens were myelin basic protein (MBP), myelin-associated glycoprotein (MAG), ganglioside (GM1), sulfatide (SULF), chondroitin sulfate (CONSO4), myelin oligodendrocyte glycoprotein (MOG), alpha,beta-crystallin (alpha,beta-CRYS), neurofilament proteins (NAFP), tubulin and three cross-reactive peptides, Chlamydia pneumoniae (CPP), streptococcal M protein (STM6P) and milk butyrophilin (BTN). Autistic children showed the highest levels of IgG, IgM and IgA antibodies against all neurologic antigens as well as the three cross-reactive peptides. These antibodies are specific because immune absorption demonstrated that only neuron-specific antigens or their cross-reactive epitopes could significantly reduce antibody levels. These antibodies may have been synthesized as a result of an alteration in the blood-brain barrier. This barrier promotes access of preexisting T-cells and central nervous system antigens to immunocompetent cells, which may start a vicious cycle. These results suggest a mechanism by which bacterial infections and milk antigens may modulate autoimmune responses in autism.

Antigens↗
PubMed1994

Neuron-specific expression of the synapsin II gene is directed by a specific core promoter and upstream regulatory elements.

Synapsin II is an abundant peripheral membrane protein of synaptic vesicles that is expressed exclusively in neuronal cells. Here we report the isolation and characterization of the 5'-terminal region of the murine synapsin II gene. Primer extension and S1 nuclease protection analysis show that synapsin II gene transcription is initiated from a unique site. The synapsin II gene promoter contains no canonical TATA or CAAT boxes but has putative binding sites for the transcription factors Sp1, AP2, and NGFIA. This promoter is embedded in a large G+C-rich domain with characteristics of a CpG island. Transfection experiments using synapsin II-luciferase fusion genes demonstrate that the 5'-flanking sequence functions as a strong promoter in neuronal but not in nonneuronal cells. Deletion analysis reveals the presence of a neuron-specific core promoter (-79 to 153) and, upstream, two positive and one negative regulatory elements. The 5'-terminal region of the murine synapsin I gene was also cloned and sequenced. Although there is no extensive sequence homology between the 5'-flanking regions of the synapsin I and II genes, comparison analysis has identified two regions of homologous sequences, which may be involved in determining neuron specificity of the core promoters of these two genes.

Amino Acid Sequence↗
PubMed1997

Expression of two neuronal markers, growth-associated protein 43 and neuron-specific enolase, in rat glial cells.

Recent studies have revealed that proteins such as growth-associated protein 43 (GAP-43) and neuron-specific enolase (NSE), believed for many years to be expressed exclusively in neurons, are also present in glial cells under some circumstances. Here we present an overview of these observations. GAP-43 is expressed both in vitro and in vivo transiently in immature rat oligodendroglial cells of the central nervous system, in Schwann cell precursors, and in non-myelin-forming Schwann cells of the peripheral nervous system. GAP-43 mRNA is also present in oligodendroglial cells and Schwann cells, indicating that GAP-43 is synthesized in these cells. GAP-43 is also expressed in type 2 astrocytes (stellate-shaped astrocytes) and in some reactive astrocytes but not in type 1 astrocytes (flat protoplasmic astrocytes). These results suggest that GAP-43 plays a more general role in neural plasticity during development of the central and peripheral nervous systems. NSE enzymatic activity and protein and mRNA have been detected in rat cultured oligodendrocytes at levels comparable to those of cultured neurons. NSE expression increases during the differentiation of oligodendrocyte precursors into oligodendrocytes. In vivo, NSE protein is expressed in differentiating oligodendrocytes and is repressed in fully mature adult cells. The upregulation of NSE in differentiating oligodendrocytes coincides with the formation of large amounts of membrane structures and of protoplasmic processes. Similarly, NSE becomes detectable in glial neoplasms and reactive glial cells at the time when these cells undergo morphological changes. The expression of the glycolytic isozyme NSE in these cells, which do not normally contain it, could reflect a response to higher energy demands. This expression may also be related to the neurotrophic and neuroprotective properties demonstrated for this enolase isoform. NSE activity and protein and mRNA have also been found in cultured rat type 1-like astrocytes but at much lower levels than in neurons and oligodendrocytes. Thus GAP-43 and NSE should be used with caution as neuron-specific markers in studies of normal and pathological neural development.

Animals↗
PubMed1989

[Two cases of Creutzfeldt-Jakob disease with high neuron-specific enolase level in cerebrospinal fluid].

Because neuron-specific enolase (NSE), one of the distal branch enzyme of Embden-Myerhof glycolytic pathway is abundant in the neuronal cytoplasm and axons, the measurement of its level in cerebrospinal fluid (CSF) would be useful in diagnosis and consideration of pathophysiology in various neurological diseases. The Creutzfeldt-Jakob disease (CJD) in which neuronal destruction is usually prominent pathologically, has so far been thought to reveal no abnormalities in CSF. In the two cases of CJD, we conducted the time sequential measurement of NSE level in CSF and compared it with serum NSE and CSF lactate levels. We found that the CSF NSE level was high in the early stage of this disease, at which time the brain CT showed no or minimal abnormalities, followed by gradual increase up to the maximum level when myoclonus and periodic synchronous discharge appeared in electroencephalogram. Then, the CSF NSE level decreased in parallel with the progression of brain atrophy in CT scan and finally on the late stage, the CSF NSE level fell within normal range. Serum NSE and CSF lactate levels were mildly elevated in all stages of this disease, but were not parallel to the disease activity. This implies that the CSF NSE level can serve as a marker for the presence of active process in neuronal destruction. Again the CSF NSE level was elevated in both cases even from the very early stage when the typical clinical manifestations of this disease were absent. Therefore, the results of this study provided us with an important indicator for the early stage diagnosis of CJD.

Aged↗
PubMed1986

Rapid electrophoretic determination of neuron-specific enolase isoenzymes in serum.

This assay procedure for each of the two neuron-specific enolases (alpha gamma and gamma gamma) and the non-neuronal enolase (alpha alpha) in serum involves two steps: electrophoretic separation of the three isoenzymes--alpha alpha, alpha gamma, and gamma gamma--on cellulose acetate, and bioluminescence measurement of total enolase activity. From these data, the activity concentrations (U/L) of the three isoenzymes in serum are calculated. Both measurement steps are based on the enzymatic activity of enolase and thus differ from the immunological methods currently in use, which require the availability of specific antibodies. The method is rapid (approximately 30 min for both steps) and requires only 10 microL of serum for the complete analysis. Studies of normal children and adults, and of patients suffering from neuroblastoma and small-cell lung cancer, show that it is suitable for clinical use. Furthermore, the fact that both neuron-specific isoenzymes of enolase can be systematically separated is an advantage over immunological techniques in determining isoenzyme patterns for pathological samples.

Adult↗
PubMed1987

High neuron-specific enolase level of cerebrospinal fluid in the early stage of Creutzfeldt-Jakob disease.

The measurement of neuron-specific enolase level in serum and cerebrospinal fluid was conducted time-sequentially in an autopsy confirmed patient with Creutzfeld-Jakob disease. The level was markedly high in the early stage of the disease at which time the brain CT showed no or minimal abnormalities, while falling into the normal range in the advanced stage. This is the first report of the elevated level of neuron-specific enolase in Creutzfeldt-Jakob disease.

Aged↗
PubMed1999

Regulation of the neuron-specific exon of clathrin light chain B.

Clathrin light chain B (LCB) is a major component of clathrin coated vesicles, which are structures involved in intracellular transport. A neuron-specific isoform of LCB is generated by incorporation of a single exon (EN) using an alternative splicing mechanism that reflects the special demands of neurons, such as axonal transport and synaptic neurotransmission. Here, we demonstrate that this neuron-specific exon is developmentally regulated and is excluded in non-neuronal cells because its 5' and 3' splice sites deviate from the mammalian consensus sequences. A gel retardation assay indicated the presence of a developmentally regulated factor in brain that binds to the neuronal exon. In addition, EN usage is repressed by increasing the concentration of htra2-beta1, a splice factor whose isoform expression is influenced by neuronal activity. We propose that a brain-specific factor is involved in EN recognition during development and adulthood. In addition, ubiquitously expressed splicing factors such as htra2-beta1 are involved in regulating EN expression in the adult brain.

Age Factors↗
PubMed1997

Sequences in the proximal 5' flanking region of the rat neuron-specific enolase (NSE) gene are sufficient for cell type-specific reporter gene expression.

We investigated the regulation of the rat neuron-specific enolase gene using a transient transfection approach. Recent transgenic mouse studies have shown that a 1.8-kb segment of the rat NSE gene 5' flanking region, including the first (noncoding) exon but not the first intron, is able to drive expression of a reporter gene in parallel with endogenous NSE. These data suggest that cis-acting elements responsible for the spatial and temporal pattern of NSE gene expression are located within the proximal 1.8 kb of the 5' flanking sequence. To further investigate this region, we joined the 1.8-kb regulatory cassette to the cat reporter gene and generated a number of constructs in which the flanking sequence was progressively deleted from the 5' end. These constructs were tested by transient transfection into neuronal and nonneuronal cells, followed by an assay for CAT activity. We found that as little as 255 bp of 5' flanking sequence was able to confer cell type-specificity on the reporter gene. Further truncation to 120 bp of 5' sequence resulted in a sharp downregulation of reporter activity in PC12 cells but a significant rise in both Neuro-2A neuroblastoma cells and nonneuronal Ltk- cells, indicating that cis-acting elements controlling the regulation of NSE in Ltk-, Neuro-2A, and PC12 cells may lie within the 135 bp region covered by this deletion. This region contains an AP-2 site and an element similar in sequence and position to a motif identified in the proximal promoter region of the neuron-specific peripherin gene. Reduction to 95 bp of 5' sequence resulted in a slight downregulation of CAT activity in all cell lines tested, and further truncation to 65 bp of 5' sequence caused a universal reduction to background levels of CAT activity, concomitant with the disruption of the basal NSE promoter. Our results show that the 5' flanking region of the NSE gene is capable of conferring cell type-specificity on a heterologous gene in transfected cells and that elements responsible for this are located within the proximal 255 bp.

Animals↗
PubMed2004

Serous cystic neoplasms of the pancreas: an immunohistochemical analysis revealing alpha-inhibin, neuron-specific enolase, and MUC6 as new markers.

Serous cystic neoplasms (SCNs) of the pancreas include serous microcystic adenoma (SMA), serous oligocystic ill-demarcated adenoma (SOIA), solid serous adenoma (SSA), von Hippel-Lindau-associated cystic neoplasm (VHL-CN), and serous cystadenocarcinoma (SCC). These neoplasms are histologically similar but differ in their localization, gross appearance, gender distribution, and biology. A centroacinar origin is assumed but has not been proven. To clarify whether the various subtypes of SCN may be distinguished from each other by marker profiles that might also provide evidence of their origin, the immunoprofiles of 38 SCNs (21 SMAs, 13 SOIAs, 2 VHL-CNs, 1 SSA, and 1 SCC) were defined by applying antibodies against cytoskeletal, neuroendocrine, hormone receptor, and mucin markers. In addition, we examined the expression of calretinin and alpha-inhibin. The various types of SCN showed a very similar immunoprofile, characterized by positivity for cytokeratins and neuron-specific enolase and negativity for vimentin and synaptophysin. Further markers that were commonly expressed in SCNs were alpha-inhibin (SMAs: 76%, SOIAs: 92%, VHL-CNs: 100%), MUC6 (SMAs: 60%, SOIAs: 85%, VHL-CNs: 100%), and MUC1 (SMAs: 24%, SOIAs: 38%, VHL-CNs: 50%). Western blot analysis in one SMA revealed a distinct band that stained with neuron-specific enolase antiserum. Alpha-inhibin was only expressed in 4 of 11 acinar cell carcinomas and not in five ductal adenocarcinomas, five neuroendocrine tumors, one mixed ductal-endocrine carcinoma, and one acinar cell cystadenoma of the pancreas. These results suggest that, despite their biologic differences, the various types of SCNs are composed of the same (or a very similar) cell type and may therefore have a common direction of differentiation. This notion is further supported by the finding that neuron-specific enolase, alpha-inhibin, and MUC6, which may be regarded as new markers for this pancreatic tumor type, were also expressed in most SCNs. Because a number of SCNs share MUC1 and MUC6 expression with the pancreatic centroacinar cells, the possibility of a histogenetic relationship has to be considered.

Adult↗
PubMed1994

Expression of neuron-specific tubulin defines a novel population in the proliferative layers of the developing telencephalon.

We have used a monoclonal antibody against the neuron-specific class III beta-tubulin (TuJ1; Lee et al., 1990b) to study the distribution and morphology of immature neurons in the proliferative ventricular and subventricular zones of the developing telencephalon. Mouse brains from embryonic day 12 (E12) to postnatal day 5 (P5) were fixed either with a non-cross-linking agent, HistoChoice, or with 4% paraformaldehyde, and processed for TuJ1 immunohistochemistry. TuJ1 immunoreactivity first appeared in the proliferative zones of the developing cerebral cortex at E13-E14 as the cortical plate was emerging. After E14, tangentially oriented TuJ1-positive cells were abundant at the interface between the ventricular and subventricular zones. This tangential pattern was less conspicuous in the developing striatum. Within the cortical and striatal ventricular zone TuJ1-positive cells were less numerous and displayed a variety of orientations and morphologies. Postnatally, after the period of neurogenesis has ended, TuJ1 immunoreactivity continued to increase in the subventricular zone and remained high until the last developmental stage examined (P5). Anti-MAP2, another neuron-specific marker, never labeled the cells of the ventricular and subventricular zones, pre- or postnatally. To determine the birthdates of TuJ1-positive cells in the cortical-ventricular and subventricular zones, brains were double labeled with TuJ1 and bromodeoxyuridine according to different pulse-chase schedules. TuJ1-positive cells were postmitotic and generated throughout the period of cortical neurogenesis. Collectively, the results suggest that TuJ1 immunoreactivity distinguishes two neuronal populations: those that remain for an indefinite period of time in the proliferative zones, and those that leave the proliferative zones soon after being generated. Although the fate of the TuJ1-positive cells that reside in the proliferative zones remains unclear, their tangentially aligned orientation and their distribution suggest that they migrate independent of radial glial fibers.

Aging↗
PubMed1989

Neuron-specific enolase (NSE) as a neuroendocrine cell marker in the human fetal pancreas.

Using the PAP technique, we investigated the presence of neuron-specific enolase in the human fetal pancreas of 10, 12, and 14 weeks of gestational age. Neuron-specific enolase is present in the islet cells in the 10th week. Positive cells are situated mainly in duct epithelium. The number of cells with a positive reaction increases from the 12th to the 14th week. In the 14th week, they are clustered either near the ducts or between the acini. The numbers and localizations of the cells correspond to those obtained in previous studies with 4 basic islet cell types in the same material. The present results are a further proof that islet cells are biologically active during early fetal development.

Biomarkers↗
PubMed1989

Co-localization of neuron-specific enolase-like and kallikrein-like immunoreactivity in ductal and tubular epithelium of sheep salivary gland and kidney.

Neuron-specific enolase-like and kallikrein-like immunoreactivity was found to be co-localized in the ductal elements of the submandibular gland and in the more distal portions of the nephron in the kidney of newborn lambs. Some glomerular peripolar cells in the kidney were immunopositive for neuron-specific enolase without detectable kallikrein-like immunoreactivity.

Animals↗
PubMed1987

Sequence conservation in the 3'-untranslated regions of neurone-specific enolase, lymphokine and protooncogene mRNAs.

The C-terminal protein-coding and the entire 3'-untranslated regions of a cDNA corresponding to human neurone-specific enolase mRNA have been sequenced. The 3'-untranslated region is 892 bases long and shows a high degree of homology with the 3'-untranslated region of rat neurone-specific enolase mRNA. This sequence conservation is not seen in non-neuronal enolase mRNAs. Features of the conserved sequence include an A-rich region approx. 250 bases from the stop codon at a point corresponding to the polyadenylation signal site in non-neuronal enolase mRNA, and a repeating ATTT sequence. This unusual motif in eukaryotic mRNAs has previously been reported in the 3'-untranslated regions of lymphokine and protooncogene mRNAs.

Amino Acid Sequence↗
PubMed1993

Vomeronasal epithelial cells of the adult human express neuron-specific molecules.

Immunohistochemical localization of three molecular markers, neuron-specific enolase (NSE) and protein gene product (PGP) 9.5 for neurons and neuroendocrine cells, and olfactory marker protein (OMP) for olfactory receptor neurons (ORNs) was investigated in the vomeronasal epithelium (VNE) of adult humans. NSE- and PGP 9.5-immunoreactive cells were identified in the VNE. ORNs in the olfactory epithelium of approximately age-matched controls were immunoreactive for the three markers. Most NSE-immunoreactive cells in the VNE were bipolar and similar in shape to the NSE- and PGP 9.5-immunoreactive ORNs. The results indicate that the adult human VNE contains cells expressing two molecular markers characteristic of neurons and that these cells bear a striking morphological similarity to ORNs.

Adult↗
PubMed1984

Localisation of histamine-immunoreactivity in specific neurones of the gastropod CNS including a cell which has been identified as histaminergic.

Immunohistochemical procedures revealed the occurrence of histamine-like immunoreactivity in specific neurones in the gastropod nervous system. Positive staining was also associated with a characterised neurone known from previous biochemical studies to contain histamine. The proof of the restriction of histamine to specific neurones and the availability of a suitable antiserum to localise the amine makes it possible to examine the role of the compound in different nervous systems.

Animals↗