Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The site and regulation of neurotrophic factor release from neurons is poorly understood. We used a combination of model cell lines and primary culture systems to study the polarity of BDNF sorting and the regulation of its release from hippocampal neurons. Transfection and expression of a human BDNF cDNA in a mouse pituitary cell line, AtT20, resulted in the colocalization of BDNF with the secretory granule marker, chromogranin A. Furthermore, stimulation of these cells with 56 mM KCl or with 5 mM 8-bromo-cAMP increased the release of BDNF approximately 10-to 15-fold within 30 min. To study BDNF release from primary cultures of hippocampal neurons, cells were infected with a defective Herpes Simplex Viral (HSV) vector expressing human BDNF. Depolarizing conditions increased the release of BDNF 5-fold from these cells, further verifying that secretion is regulated. Immunocytochemical analysis using highly specific antibodies determined that endogenous BDNF was predominantly localized to the somatodentritic domain of hippocampal neurons. These findings support the view that BDNF functions as a target-derived signal for afferents to hippocampal pyramidal cells and that it may serve as a regulator of hippocampal plasticity.
Mol Cell Neurosci 1996 Mar
PMID:Regulated release and polarized localization of brain-derived neurotrophic factor in hippocampal neurons. 872 5

The effects of neurotrophic factor on the expression of neuropeptide Y (NPY) mRNA and on morphology of NPY-immunoreactive neurons were investigated. Brain-derived neurotrophic factor (BDNF) increased the expression of NPY mRNA in cultured cortical neurons from both embryonic and postnatal rats. BDNF also increased the number of NPY neurons. Furthermore, multipolar neurites from NPY neurons were observed in cultures treated with BDNF, whereas only monopolar and bipolar neurites were observed in control cultures. These results suggest that BDNF not only increases the expression of NPY mRNA but also promotes the differentiation/maturation of NPY ergic neurons both in number and morphology. NPY expression was strongly increased by neurotrophin-4/5 similarly to BDNF and neurotrophin-3 evoked a slight increase. In contrast, basic fibroblast growth factor, cilliary neurotrophic factor and interferon-gamma had no effect on NPY expression.
Brain Res Mol Brain Res 1996 Apr
PMID:BDNF increases the expression of neuropeptide Y mRNA and promotes differentiation/maturation of neuropeptide Y-positive cultured cortical neurons from embryonic and postnatal rats. 873 62

The four established or putative sphingolipid activator proteins derive from a large precursor protein encoded by a single gene. In addition to generating the four sphingolipid activator proteins, the precursor protein is suspected of having functions of its own, as, for example, a lipid binding/transport protein or a neurotrophic factor. The gene also appears to encode the Sertoli cell major sulfated glycoprotein. Sequence similarities have been noted with many other proteins of diverse functions. One patient and a fetus in a single family with a complete defect of this gene due to a mutation in the initiation codon exhibited complex pathological and biochemical abnormalities. Mutant mice homozygous for an inactivated gene of the sphingolipid activator protein precursor exhibit two distinct clinical phenotypes-neonatally fatal and later-onset. The latter develop rapidly progressive neurological signs around 20 days and die by 35-38 days. At 30 days, severe hypomyelination and periodic acid-Schiff-positive materials throughout the nervous system and in abnormal cells in the liver and spleen are the main pathology. Most prominently lactosylceramide, and additionally ceramide, glucosylceramide, galactosylceramide, sulfatide, and globotriaosylceramide are abnormally increased in the brain, liver, kidney, and their catabolism abnormally slow in cultured fibroblasts. Brain gangliosides are generally increased, particularly the monosialogangliosides. The clinical, pathological and biochemical phenotype closely resembles that of the human disease. This model not only allows further clarification of the physiological functions of the four individual sphingolipid activator proteins but also should be useful to explore putative functions of the precursor protein.
Hum Mol Genet 1996 Jun
PMID:Targeted disruption of the mouse sphingolipid activator protein gene: a complex phenotype, including severe leukodystrophy and wide-spread storage of multiple sphingolipids. 877 85

Nerve growth factor (NGF) is a neurotrophic factor for basal forebrain cholinergic neurons, a population that degenerates and dies in Alzheimer's disease (AD). It has been suggested that NGF be used to treat AD patients. However, in vivo administration of NGF to the developing hamster brain was shown to induce the expression of the beta-amyloid precursor protein (beta APP) gene. The association of alterations in beta APP gene expression with AD-like neuropathological changes and cognitive impairment in animals, and with AD-like neurodegeneration in Down syndrome patients suggests that NGF-mediated increases in beta APP expression could negate or attenuate NGF's neurotrophic activity in AD treatment trials. The present study was undertaken to explore further the influence of NGF on beta APP expression, and to determine which, if any, of the beta APP mRNAs is altered in response to NGF treatment. We first examined the spatiotemporal pattern of beta APP-695 and Kunitz protease inhibitor (KPI)-containing beta APP mRNA expression in the rat brain. Specific oligonucleotide probes were used to show that these mRNAs are present during embryonic development. In addition, we evaluated postnatal expression in nine brain regions and showed that beta APP mRNAs were readily detected in all regions at postnatal day 2. In human brain, the relative levels of beta APP-695 and beta APP-KPI mRNA and their protein are discordant, in that the level of beta APP-695 mRNA is slightly higher than that of beta APP-KPI, but beta APP-KPI protein predominates. In contrast, the several-fold excess of beta APP-695 mRNA relative to beta APP-KPI mRNA in the rat brain was also reflected at the protein level. Surprisingly, administration of exogenous NGF failed to affect rat beta APP mRNA levels either in vitro or during postnatal development in vivo.
Brain Res Mol Brain Res 1996 Jul
PMID:A comprehensive study of the spatiotemporal pattern of beta-amyloid precursor protein mRNA and protein in the rat brain: lack of modulation by exogenously applied nerve growth factor. 880 27

We previously reported that the total neurotrophic activity of hippocampal extracts was significantly (25-50%) reduced after 21-28 weeks of chronic ethanol treatment (CET) [23]. To test whether the level of a neurotrophic factor (i.e., ligand itself) is compromised, we measured nerve growth factor (NGF) protein and NGF mRNA contents using ELISA and Northern analysis. We reported that CET did not appear to reduce NGF protein, NGF mRNA or total neurotrophic activity when measured on sympathetic ganglia neurons [4]. We also observed that both NT-3 mRNA and bFGF mRNA levels were unaffected, but the BDNF mRNA levels was significantly reduced in CET rat hippocampus [18]. Neuronal degeneration and reduction of total neurotrophic activity after CET appear to be induced, at least partially, by compromised transcription of BDNF gene. CET may also induce functional changes in receptors for the neurotrophic factors. To investigate possible changes in neurotrophic factor-receptors, we examined Western blots (immunoblots) of rat cortex after 28 weeks of CET. After sonication and ultra-centrifugation, the supernatant of crude lysates of the cortex from individual animals was subjected to SDS-PAGE, electrotransfered to nitrocellulose membrane, incubated with anti-trk B antibody and secondary antibody conjugated to alkaline phosphatase, and reacted with chemiluminescent substrate. The membranes were then exposed to Kodak XAR film. Compared to controls (n = 6), CET rats (n = 6) appeared to have significantly higher band intensity (P < 0.01) of trk B-like protein at about 145 kDa, which suggests an up-regulation of trk B-like proteins to compensate the compromised level of certain subset (i.e., BDNF or NT-4/5, but not NGF) of neurotrophins in cortex.
Brain Res Mol Brain Res 1996 Aug
PMID:Up-regulation of high-affinity neurotrophin receptor, trk B-like protein on western blots of rat cortex after chronic ethanol treatment. 884 27

We have now applied the enzyme immunoassay using anti-NGF monoclonal antibody (MAb) 27/21 and a blocking test validating the specificity of the immunoreactivity for NGF in serum samples to examine NGF levels in normal rat sera, hemiparkinsonian rat sera, normal monkey sera, and MPTP-treated monkey sera. The levels of NGF in treated animals showed reductions when compared with serum from normal animals. The NGF level alterations observed in lesioned animals and in human parkinsonian patients evidence a relationship between this neurotrophic factor and the neurodegenerative changes observed in Parkinson disease (PD).
Mol Chem Neuropathol
PMID:NGF in experimental models of Parkinson disease. 887 63

Glia cell line-derived neurotrophic factor (GDNF), a recently cloned member of the transforming growth factor-beta (TGF-beta) superfamily, has been implicated in the survival, morphological and functional differentiation of midbrain dopaminergic neurons and motoneurons in vitro and in vivo. The factor may thus have utility in the treatment of various human neurodegenerative disorders. Mechanisms regulating expression of GDNF in normal and diseased brain as a possible means to increase the local availability of GDNF are only beginning to be explored. We have established and employed a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) to study and compare levels of expression of GDNF mRNA in several cell types and to investigate its regulation. GDNF expression was clearly evident in primary cultured astrocytes, the glioma B49 and C6 cell, but less pronounced in the Schwannoma RN22 cell lines. Little or no signal could be observed in neuroblastoma cell lines (IMR32, LAN-1) or the pheochromocytoma cell line PC12, emphasizing the glial character of this factor. Using the C6 cell line we found that fibroblast growth factor-2 (FGF-2; bFGF) can increase GDNF mRNA levels, whereas FGF-1, platelet-derived growth factor (PDGF), and vasoactive intestinal polypeptide (VIP) are apparently ineffective. Several other factors (forskolin, kainic acid, triiodothyronine dexamethasone, GDNF, TGF-beta 1, and interleukin-6) appear to have slightly negative effects on GDNF mRNA levels at the concentrations tested. To further explore the relationship between FGF-2 and GDNF, we also addressed the question whether GDNF, like FGF-2, may have an effect on C6 cell proliferation. We conclude that (1) glial and glial tumor cells, rather than neuronal cell lines, express GDNF, (2) that FGF-2 has a prominent inductive effect on GDNF expression and (3) that GDNF stimulates C6 cell proliferation. Finally, these data suggest that neurotrophic actions of FGF-2 in mixed glial-neuronal cell cultures might be mediated in part by GDNF.
Brain Res Mol Brain Res 1996 Sep 05
PMID:GDNF mRNA levels are induced by FGF-2 in rat C6 glioblastoma cells. 888 50

To understand and intervene in neuronal cell death, intensive investigations have been directed at the discovery of intracellular and extracellular factors that provide natural neuroprotection. This goal has fundamental importance for both rational strategies for the treatment of neurodegenerative diseases and also the delineation of molecular mechanisms that regulate nervous system differentiation and growth. We have discovered a potential interface among these fields of research with activity-dependent neurotrophic factor (ADNF), a protein containing sequence homologies to intracellular stress proteins that is found in the extracellular milieu of astroglial cells incubated with the neuropeptide vasoactive intestinal peptide (VIP). Femtomolar concentrations of ADNF and a short peptide sequence derived from it (a peptidergic active site) protected neurons from death associated with a broad range of toxins, including those related to Alzheimer's disease, the human immunodeficiency virus, excito-toxicity, and electrical blockade. Because the activity of the protein was mimicked by a short peptide fragment, this peptide is now proposed as a lead compound for drug development against neurodegeneration.
J Mol Neurosci 1996
PMID:Activity-dependent neurotrophic factor (ADNF). An extracellular neuroprotective chaperonin? 896 45

The CSF-1 null mouse, osteopetrotic, has provided a powerful model in which to study the biological functions of CSF-1. In this review, I will describe our studies that have used this mouse model to determine the impact of a lack of CSF-1 on developmental processes and in reproduction. A role for CSF-1 in reproduction was originally suggested by the sex steroid hormone-regulated uterine epithelial synthesis of CSF-1 and the expression of its receptor in trophoblast and decidual cells. Studies on the fertility of CSF-1 deficient osteopetrotic mice (csfmop/csfmop) mice confirmed this suggestion and in addition revealed an unexpected function for CSF-1 in male fertility. In both sexes, CSF-1 appears to regulate gonadal steroidogenesis, probably through its action on macrophages that are abundant throughout the ovary and testis. In the female, CSF-1 affects ovulation in vivo and in vitro, and impacts the preimplantation embryo, increasing both its rate of development and the number of trophectodermal cells in the blastocyst. CSF-1 also has a role in mammary gland development during pregnancy, since at mid-gestation in csfmop/csfmop mice, ductal branching is impaired, and after partiturition, there is a failure to switch to lactation. The relative failure of csfmop/csfmop mice to respond to external stimuli also suggested a role for CSF-1 in the brain. CSF-1 mRNA is expressed in a regional specific manner in the brain through development whilst the CSF-1 receptor is expressed throughout the brain in microglia. CSF-1 is neurotrophic in embryonic neuronal cultures and its absence in csfmop/csfmop mice results in severe electro-physiological abnormalities in the cortex. This suggests that CSF-1 is a neurotrophic factor acting through the microglia. The pleiotropic roles for CSF-1 in reproduction and in the brain suggest that CSF-1 exerts many of its action through the trophic activities of cells of the mononuclear phagocytic lineage.
Mol Reprod Dev 1997 Jan
PMID:Role of colony-stimulating factor-1 in reproduction and development. 898 64

Nerve growth factor (NGF) is a potent regulator of sympathetic neuronal function in both developing and adult animals. This article reviews the evidence published in recent years indicating that another member of the NGF family, neurotrophin 3 (NT3), plays both a complementary and overlapping role in the development and maturation of sympathetic neurons. In migratory neural crest cells, expression of the high-affinity receptor, trkC, and promotion of mitosis by NT3 suggest an involvement in gangliogenesis, since sympathetic neuroblasts express both NT3 and trkC and require NT3 for their proliferation, differentiation, and survival, it has been proposed that the factor acts at this developmental stage as an autocrine or paracrine factor. However, NT3 also acts in parallel with NGF to promote the survival of postmitotic neurons during late development. Both trkC and trkA are expressed in sympathetic neurons and function as high-affinity receptors for NT3. NT3 is synthesized in sympathetic effector tissues and the endogenous factor is retrogradely transported to accumulate within the cell soma. Thus, in addition to its role in the differentiation of sympathetic neurons, NT3, like NGF, is also an effector tissue-derived neurotrophic factor for these neurons in maturity.
Mol Neurobiol 1996 Dec
PMID:Functional roles of neurotrophin 3 in the developing and mature sympathetic nervous system. 898 69


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