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PubMed1993

Neuron-specific expression of the human dopamine beta-hydroxylase gene requires both the cAMP-response element and a silencer region.

Dopamine beta-hydroxylase (DBH), the enzyme catalyzing the conversion of dopamine to norepinephrine, is specifically expressed in adrenergic and noradrenergic neurons in the central nervous system. DNase I hypersensitive sites were found in the 5'-flanking region of the DBH gene in noradrenergic human neuroblastoma SK-N-BE(2)C cells, but not in DBH-nonexpressing HeLa cells. We report here that the 4.3-kilobase upstream sequence of the human DBH gene confers cell type-specific expression as assessed by transient expression assay. Furthermore, deletional and mutational analyses revealed two genetic regulatory elements required for the regulation of cell type specificity. First, deletion of the cAMP-response element (CRE) abolished > 95% of the transcriptional activity by the DBH upstream promoter, thus implicating the CRE as an essential positive genetic element. Second, deletion of a region between -490 and -263 base pairs resulted in 10-fold increase of reporter gene activity only in HeLa cells, indicating that this region contains a cell-specific silencer. A 13-base pair fragment residing within that region shows 77% sequence identity with the neuron-specific silencer motif recently identified in two neuronal genes, i.e. SCG10 and type II sodium channel genes. We propose that the interplay between the CRE and this neuron-specific silencer region plays an important role in the tissue-specific expression of the DBH gene in noradrenergic cells.

Animals↗
PubMed1990

Serum neuron-specific enolase is a useful tumor marker for small cell lung cancer.

Small cell lung cancer (SCLC) may be potentially curable. A correct diagnosis of cancer cell type is important and serum markers are of great value. Although several markers have been suggested, they have been of limited value because of insufficient specificity. To assess the value of serum neuron-specific enolase (S-NSE) as a possible marker of SCLC, the serum levels of 81 patients with SCLC (59 patients with extensive disease and 22 patients with limited disease) were compared with the serum levels of patients with non-small cell lung cancer (N-SCLC) and 93 patients with nonmalignant lung diseases. The S-NSE level also was measured in 104 patients with extensive disease of various other malignancies, including 71 solid tumors and 33 malignant hematologic disorders. From 105 healthy control subjects, the upper limit of the normal range (x + 2 standard deviations [SD]) was determined as 12.3 ng/ml. The S-NSE level was elevated in 78% of patients with SCLC, including 11 of 22 (50%) with limited disease and 52 of 59 (88%) with extensive disease. In contrast, the S-NSE level was raised only in 18% of patients with advanced N-SCLC (nine of 50) and 6% of patients with nonmalignant lung diseases (six of 93). Twelve patients (17%) with other solid malignant tumors and two patients (6%) with malignant hematologic disorders had raised S-NSE levels. Serial N-NSE levels were obtained in 13 patients with SCLC. S-NSE levels fell in all patients responding to chemotherapy and increased again with progression of disease. Our results indicate that S-NSE seems to be specific for SCLC (85%), whereas sensitivity seems to be dependent on the stage of disease. Further, S-NSE may be a useful marker for monitoring treatment and predicting relapse in patients with SCLC.

Biomarkers, Tumor↗
PubMed1990

Delay, discriminatory, and modality specific neurons in striatum and pallidum during short-term memory tasks.

The function of the striatum and its integrative capacities is addressed. The activity of single neurons in behaving Macaca mulatta is studied. Two new classes of neurons were found. In the striatum, but not in the pallidum, these neurons were visual modality specific. These neurons may represent a conjunction of sensory, mnemonic and motor information, and may be concerned with decisions about the emission or withholding of movements. The frontal dysfunction hypothesis of cognitive deficits in Parkinson's disease is considered.

Animals↗
PubMed2003

Adaptive evolution of MRG, a neuron-specific gene family implicated in nociception.

The MRG gene family (also known as SNSR) belongs to the G-protein-coupled receptor (GPCR) superfamily, is expressed specifically in nociceptive neurons, and is implicated in the modulation of nociception. Here, we show that Ka/Ks (the ratio between nonsynonymous and synonymous substitution rates) displays distinct profiles along the coding regions of MRG, with peaks (Ka/Ks>1) corresponding to extracellular domains, and valleys (Ka/Ks<1) corresponding to transmembrane and cytoplasmic domains. The extracellular domains are also characterized by a significant excess of radical amino acid changes. Statistical analysis shows that positive selection is by far the most suitable model to account for the nucleotide substitution patterns in MRG. Together, these results demonstrate that the extracellular domains of the MRG receptor family, which presumably partake in ligand binding, have experienced strong positive selection. Such selection is likely directed at altering the sensitivity and/or selectivity of nociceptive neurons to aversive stimuli. Thus, our finding suggests pain perception as an aspect of the nervous system that may have experienced a surprising level of adaptive evolution.

Adaptation, Physiological↗
PubMed2003

Use of neuron-specific enolase for assessing the severity and outcome in patients with neurological disorders.

Neuron-specific enolase (NSE) is a glycolytic enzyme present almost exclusively in neurons and neuroendocrine cells. NSE levels in cerebrospinal fluid (CSF) are assumed to be useful to estimate neuronal injury and clinical outcome of patients with serious clinical manifestations such as those observed in stroke, head injury, anoxic encephalopathy, encephalitis, brain metastasis, and status epilepticus. We compared levels of NSE in serum (sNSE) and in CSF (cNSE) among four groups: patients with meningitis (N=11), patients with encephalic injuries associated with impairment of consciousness (ENC, N=7), patients with neurocysticercosis (N=25), and normal subjects (N=8). Albumin was determined in serum and CSF samples, and the albumin quotient was used to estimate blood-brain barrier permeability. The Glasgow Coma Scale score was calculated at the time of lumbar puncture and the Glasgow Outcome Scale (GOS) score was calculated at the time of patient discharge or death. The ENC group had significantly higher cNSE (P=0.01) and albumin quotient (P=0.005), but not sNSE (P=0.14), levels than the other groups (Kruskal-Wallis test). Patients with lower GOS scores had higher cNSE levels (P=0.035) than patients with favorable outcomes. Our findings indicate that sNSE is not sensitive enough to detect neuronal damage, but cNSE seems to be reliable for assessing patients with considerable neurological insult and cases with adverse outcome. However, one should be cautious about estimating the severity of neurological status as well as outcome based exclusively on cNSE in a single patient.

Adolescent↗
PubMed2004

In vivo transgene expression using an adenoviral tetracycline-regulated system with neuron-specific enolase promoter.

A recombinant adenoviral tetracycline-regulated system with neuron-specific enolase (NSE) promoter was injected stereotaxically into the striatum of rat brains. The efficiency of in vivo transfection was quantified by counting the number of green fluorescent protein (GFP)-positive cells at 3 days, 1 week, and 4 weeks after injection. NeuN immunohistochemistry demonstrated that expression of gammaPKC-GFP was dominant (20-99%) in neuron and expression of gammaPKC-GFP in neuron was significantly higher in pups than adult rats. These results indicate that tetracycline-inhibitable transcription factor (tTA) can drive tetracycline-responsive promoter (TetOp) under the control of NSE promoter, thereby efficiently and selectively expressing gammaPKC-GFP in neurons in vivo.

Adenoviridae↗
PubMed2006

Noradrenergic neuron-specific overexpression of nNOS in cardiac sympathetic nerves decreases neurotransmission.

Gene transfer of neuronal nitric oxide synthase (nNOS) with nonspecific adenoviral vectors can cause promiscuous transduction. We provide direct evidence that nNOS targeted only to cardiac sympathetic neurons inhibits sympathetic neurotransmission. An adenovirus constructed with a noradrenergic neuron-specific promoter (PRSx8), driving nNOS or enhanced green fluorescence protein (eGFP) gene expression caused exclusive expression in tyrosine hydroxylase (TH) positive rat cardiac sympathetic neurons. There was no detectable leakage of transgene expression in other cell types in the preparation nor did the transgene express in choline acetyltransferase (CHAT)-positive intracardiac cholinergic ganglia. Functionally, Ad.PRS-nNOS gene transfer increased nNOS activity and significantly reduced norephinephrine release evoked by field stimulation of isolated right atria. These effects were reversed by the NOS inhibitor N(omega)-Nitro-L-arginine. Our results demonstrate that noradrenergic cell-specific gene transfer with nNOS can inhibit cardiac sympathetic neurotransmission. This targeted technique may provide a novel method for reducing presynaptic sympathetic hyperactivity.

Adenoviridae↗
PubMed1990

Studies of neuron-specific enolase levels in serum and cerebrospinal fluid of children with neurological diseases.

Neuron-specific enolase (NSE) has recently proved to be a useful marker of neuron damage. We determined NSE levels in the serum and CSF of 117 children with various neurological disorders (43 with febrile convulsion, 25 with seizure disorder, 32 with meningitis, 3 with brain tumor, 2 with Reye syndrome, 3 with congenital CNS malformation and 9 with other disorders). The purpose of this study is to assess the potential usefulness of NSE in diagnosis and prognosis. Twenty CSF and serum samples of children without neurological problem served as a control. The mean values of the NSE levels in the CSF and serum of the control group were 5.00 +/- 1.65 ng/ml and 8.34 +/- 4.40 ng/ml respectively. The peak values were found in cases with brain tumor. A patient died of Reye syndrome didn't show a very high level of NSE in the serum or CSF. However, we found significant differences in NSE levels between the patients with febrile convulsions and those with seizure disorders (non-febrile, abnormal EEG). Most of our patients with febrile convulsions were cases of simple febrile convulsion, and their NSE levesin the CSF and serum were 4.55 +/- 1.00 and 8.06 +/- 3.18 ng/ml. Cases with non-febrile seizure disorders had significantly higher level of NSE in both CSF and serum (P less than 0.05). Patients with purulent meningitis usually had higher levels than those with aseptic meningitis. Our study can be summarized thus: 1. A normal level of NSE does not exclude severe neuron damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain↗
PubMed1993

Olf-1-binding site: characterization of an olfactory neuron-specific promoter motif.

We report characterization of several domains within the 5' flanking region of the olfactory marker protein (OMP) gene that may participate in regulating transcription of this and other olfactory neuron-specific genes. Analysis by electrophoretic mobility shift assay and DNase I footprinting identifies two regions that contain a novel sequence motif. Interactions between this motif and nuclear proteins were detected only with nuclear protein extracts derived from olfactory neuroepithelium, and this activity is more abundant in olfactory epithelium enriched in immature neurons. We have designated a factor(s) involved in this binding as Olf-1. The Olf-1-binding motif consensus sequence was defined as TCCCC(A/T)NGGAG. Studies with transgenic mice indicate that a 0.3-kb fragment of the OMP gene containing one Olf-1 motif is sufficient for olfactory tissue-specific expression of the reporter gene. Some of the other identified sequence motifs also interact specifically with olfactory nuclear protein extracts. We propose that Olf-1 is a novel, olfactory neuron-specific trans-acting factor involved in the cell-specific expression of OMP.

Aging↗
PubMed1987

Localization of neuron-specific (gamma gamma) enolase in proliferating (supportive and neoplastic) Schwann cells. An immunohisto- and electron-immunocyto-chemical study of ganglioneuroblastoma and schwannomas.

Neuron-specific (gamma gamma) enolase, a glycolytic enzyme used as a relatively specific marker for normal neurons and neuroendocrine cells, has recently been found in a variety of neoplastic cells and in reactive astrocytes. Its localization was investigated by immunohisto- and electron-immunocyto-chemistry, in the proliferating supportive Schwann cells of a peripheral ganglioneuroblastoma and in the neoplastic Schwann cells of four acoustic tumours. By light microscopy, the neoplastic Schwann cells showed moderate uneven diffuse immunopositivity for enolase. By electron-immunocytochemistry, both types of Schwann cells demonstrated immunopositivity discretely limited to their cell surface membranes. The neoplastic ganglion cells and axons of the ganglioneuroblastoma and the normal neurons and axons included in the schwannomas were, as expected, intensely immunopositive. The visualization of gamma gamma enolase on the cell surface membranes of both neoplastic and non-neoplastic proliferating Schwann cells suggests that increased glycolytic activity may occur on the surface of these proliferating cells irrespective of the nature of the proliferation.

Ganglioneuroma↗
PubMed2003

Neuron-specific aminopeptidase and puromycin-sensitive aminopeptidase in rat brain development.

Neuron-specific aminopeptidase (NAP) and the ubiquitous puromycin-sensitive aminopeptidase (PSA) were compared in the rat hippocampus during early development. Hippocampus contains the highest amount of NAP determined by a fast-protein liquid chromatography-aminopeptidase analyzer using Leu beta-naphthylamide as substrate. Both enzymes were found in the hippocampus in all ages. NAP was lower in immature rat; the 19th embryonic-day fetus contained the least. It increased steeply during the prenatal through the early postnatal period, 9-fold by the first month. The rate of increase diminished subsequently, increasing 20% in the second month and 13% in the third. The age-dependent increase in NAP activity was parallel to its protein expression as determined by Western blot. The specific molecular activity (hydrolytic activity/ NAP antigenicity) in newborn, 15-day-old, and 30-day-old rats were 1.00, 0.88, and 1.00, respectively. The PSA developmental profile without linear increase in activity was distinct from NAP. PSA activity was higher than NAP in decreasing order, 100-4 times, during the same development span. Similarly, different growth profiles for NAP and PSA were also found in the primary culture of developing cerebellar granule cells. Puromycin (1-5 microM) blocked neurite outgrowth and caused apoptosis by nonantibiotic effects. Our data suggest that the synaptosome-enriched NAP plays a role in neuron growth, differentiation, and information programming.

Aging↗
PubMed1981

Neuron-specific enolase in relation to differentiation in human neuroblastoma.

The presence of the two forms of enolase, neuron-specific enolase (NSE) and non-neuronal enolase (NNE), have been examined in biopsy material of human neuroblastoma, ganglioneuroblastoma, ganglioneuroma and cultured neuroblastoma cells, after separation with ion exchange chromatography. The enolase activities were inhibited in the presence of NaCl but remained active in KCl, which were used in the chromatographic step. The relative NSE levels in the neuroblastoma tissues were found to be lower than in the histopathologically more differentiated forms of the tumour, i.e. ganglioneuroblastoma and ganglioneuroma. The human neuroblastoma in vitro cell lines SK-N-SH, SH-SY5Y, SK-N-MC and IMR-32 contained considerably lower relative levels of NSE compared to the levels in the neuroblastoma biopsies. After treatment of the cultured cells with nerve growth factor or dibutyryl-cAMP some cells showed morphological differentiation and concomitantly an increase in the NSE levels. The results indicate that NSE might be useful as a marker for differentiation in human neuroblastoma.

Biopsy↗
PubMed1995

Target regulation of a motor neuron-specific epitope.

In the adult rat nervous system, motor neurons are recognized specifically by a monoclonal antibody, MO-1. Because binding by MO-1 is lost following axotomy, contact with the target may regulate this motor neuron-specific epitope. To test this hypothesis, we examined the recovery of MO-1 immunoreactivity in hypoglossal neurons following unilateral damage to the hypoglossal nerve. During the first week following nerve crush, neurons in the ipsilateral hypoglossal nucleus lost all immunoreactivity for MO-1. Antibody binding returned with time, and by 4 weeks, 80% of the injured neurons had recovered the MO-1 epitope. Since motor neurons reinnervate their original targets readily following nerve crush, it appears that MO-1 binding is recovered when motor neurons return to their original target muscles in the tongue. When the hypoglossal nerve was cut and inserted into a foreign muscle nearby (the sternomastoid muscle), the MO-1 epitope was not detected in the injured neurons, even when examined 6 weeks after surgery. However, if the sternomastoid muscle was denervated prior to insertion of the hypoglossal nerve, thus allowing the hypoglossal nerve to synapse with this foreign target, increasing numbers of hypoglossal neurons reacquired MO-1 immunoreactivity with time. Our results suggest that the MO-1 epitope is only expressed in motor neurons that are in synaptic contact with skeletal muscle. Thus, a property that distinguishes mature motor neurons from other neuronal phenotypes appears to be regulated by direct synaptic interaction with the postsynaptic target.

Animals↗
PubMed1993

Functional consequences of expression of the neuron-specific, protein kinase C substrate RC3 (neurogranin) in Xenopus oocytes.

RC3 (neurogranin) is a neuron-specific substrate of protein kinase C (PKC) that accumulates predominantly in dendritic spines of forebrain neurons and undergoes long-term potentiation (LTP)-associated increases in PKC-phosphorylation in hippocampal slices. Here the hypothesis that RC3 functions by modulating the IP3/DAG second messenger pathway after its phosphorylation by DAG-activated PKC was tested by heterologous expression in Xenopus oocytes. Acetylcholine-evoked inward chloride (Cl-) currents, dependent on both IP3 release and intracellular calcium (Ca2+), were 2- to 3-fold higher in RC3-injected oocytes than in uninjected control oocytes. RC3-oocytes did not exhibit enhanced currents when preincubated with the protein kinase inhibitor H-7 or when a glycine residue was substituted for serine, the PKC phosphorylation site of RC3. Activation of endogenous oocyte PKC by phorbol esters generated inward Cl- currents in RC3 oocytes but not in control oocytes. RC3-dependent Cl- currents were also elicited by phorbol ester in Ca(2+)-free media. We propose that PKC-phosphorylated RC3 is capable of enhancing the mobilization of intracellular Ca2+ in Xenopus oocytes and, by inference, may play a role in Ca2+ homeostasis in dendrites of forebrain neurons.

Amino Acid Sequence↗
PubMed1989

Clinical biochemistry of neuron specific enolase.

The soluble brain protein 14-3-2 first described by Moore and McGregor in 1965 is now known to be a cell specific isoenzyme of the glycolytic enzyme enolase (EC 4.2.1.11), designated neuron specific enolase (NSE). It is not only a marker for all types of neurons, but also for all neuroendocrine or paraneuronal cells. The appearance of NSE is a late event in neural differentiation, thus making NSE a useful index of neural maturation. The demonstration that tumors of the nervous system and of neuroendocrine origin contain NSE has promoted the study of NSE as a possible tumor marker. Immunocytochemistry has been used to identify NSE in cytologic preparations from several types of tumors, offering useful indications for differential diagnosis. NSE levels in serum from tumor patients are not useful in the diagnosis of early stage disease. However, serum NSE levels have been shown to be helpful in the identification of advanced small cell lung cancer, neuroblastoma and several other neoplasms. The main use of serum NSE is the monitoring of chemotherapy and the detection of a relapse in these cases.

Biomarkers, Tumor↗
PubMed1996

Immunoreactive neuron-specific enolase (NSE) is expressed in testicular carcinoma-in-situ.

Neuron-specific enolase (NSE) is a well-known marker of tumours that have neuroendocrine origin. High levels of NSE have also been described in various types of testicular germ cell neoplasms, particularly in seminomas. To evaluate the presence of NSE in testicular carcinoma-in situ (CIS), a preinvasive stage of testicular germ cell tumours, a panel of CIS tissue specimens was examined. Fifteen of 18 (83 per cent) CIS samples showed immunohistochemical staining with anti-NSE monoclonal antibody. Immunoreactivity has also been found in overt testicular germ cell tumours, including seminomas, non-seminomas, and a mixed germ cell tumour. As the co-existence of high NSE production and gene amplification of N-myc has been reported in some tumours, including germ cell tumours, the expression of the protein product of N-myc was also examined in this study, but only sporadic cases showed N-myc staining. These results are evidence against a relationship between NSE and N-myc in testicular germ cell tumours. The high expression of NSE in CIS and overt germ cell tumours may be due to the increased gene dosage effect associated with the overrepresentation of isochromosome 12p.

Adult↗
PubMed1992

Neuron-specific enolase as a prognostic factor in metastatic malignant melanoma.

Serum neuron-specific enolase (NSE) was measured in 63 patients with metastatic malignant melanoma. 20 patients (32%) had elevated serum NSE (> 10 micrograms/l) before the start of treatment. Another 13 patients (21%) developed pathological NSE values during the course of the disease. In many patients, elevated NSE was related to a large tumour burden, and a gradual rise in serum NSE indicated disease progression. Patients with elevated pretreatment NSE had a median survival time of 3 months compared with 12 months for those with normal pretreatment NSE values. NSE thus proved to be a useful prognostic factor in metastatic malignant melanoma.

Biomarkers, Tumor↗
PubMed1989

Neuron-specific enolase as a serum marker for immature teratoma and dysgerminoma.

Neuron-specific enolase (NSE) was measured with an enzyme-immunoassay in sera from 54 patients with malignant (24 cases) and benign (30 cases) germ cell tumors of ovarian origin. Serum NSE contents were clearly raised above control value (greater than 10 ng/mg) in 4 of 8 patients with immature teratomas and 5 of 6 with dysgerminomas. NSE was also measured in nine cell lines of germ cell tumors. Among these cell lines, high NSE contents were detected in the cell extracts and culture supernatants from PA-1 and Tera-II lines. In immunohistochemical study, widespread positive staining for NSE was shown in dysgerminomas, whereas the immunostaining was confined to neural elements in both an immature teratoma and xenograft tumors derived from PA-1 and Tera-II lines in nude mice. These findings suggest that serum NSE measurements are of diagnostic value not only for immature teratomas but also for dysgerminomas.

Biomarkers, Tumor↗