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)

1. Aim of the present paper is to study the expression of N-Methyl-D-Aspartate receptor (NMDAR) subunits NR2A and NR2B within mouse visual cortex. 2. To investigate the influence of neurotrophic factor of NGF family (neurotrophins) on NMDAR expression we used mutant mice carrying a deletion in the gene for brain-derived neurotrophic factor (BDNF), a well-known neurotrophin expressed in visual cortex. 3. Western blot and immunohistochemistry were performed at postnatal day P12-14, P21-23, and adulthood showing that both subunits change during postnatal development. 4. Absence of BDNF induced a reduction of NR2A level. This effect was specific since the other subunit investigated, NR2B, was not affected in mutant mice. 5. We conclude that endogenous BDNF modulates NMDAR expression in the developing visual cortex.
Cell Mol Neurobiol 2003 Apr
PMID:NR2A but not NR2B N-methyl-D-aspartate receptor subunit is altered in the visual cortex of BDNF-knock-out mice. 1273 29

Spinal muscular atrophy (SMA) is a recessive autosomal disorder characterized by degeneration of lower motor neurons caused by mutations of the survival motor neuron gene (SMN1). No curative treatment is known so far. Mutant mice carrying homozygous deletion of Smn exon 7 directed to neurons display skeletal muscle denervation, moderate loss of motor neuron cell bodies and severe axonal degeneration. These features, similar to those found in human SMA, strongly suggest the involvement of a dying back process of motor neurons and led us to test whether neurotrophic factors might have a protective role in SMA. We report here the therapeutic benefits of systemic delivery of cardiotrophin-1 (CT-1), a neurotrophic factor belonging to the IL-6 cytokine family. Intra-muscular injection of adenoviral vector expressing CT-1, even at very low dose, improves median survival, delays motor defect of mutant mice and exerts protective effect against loss of proximal motor axons and aberrant cytoskeletal organization of motor synaptic terminals. In spite of the severity of SMA phenotype in mutant mice, CT-1 is able to slow down disease progression. Neuroprotection could be regarded as valuable therapeutic approach in SMA.
Hum Mol Genet 2003 Jun 01
PMID:Therapeutic benefits of cardiotrophin-1 gene transfer in a mouse model of spinal muscular atrophy. 1276 Oct 38

We describe the discovery of a novel, 20 kDa, secreted human protein named mesencephalic astrocyte-derived neurotrophic factor, or MANF. The homologous, native molecule was initially derived from a rat mesencephalic type-1 astrocyte cell line and recombinant MANF subcloned from a cDNA encoding human arginine-rich protein. MANF selectively protects nigral dopaminergic neurons, versus GABAergic or serotonergic neurons. The discovery of MANF marks a more systematic approach in the search for astrocyte-derived, secreted proteins that selectively protect specific neuronal phenotypes. Compared to glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), MANF was more selective in the protection of dopaminergic neurons at lower (0.05-0.25 ng/mL) and middle (0.5-2.5 ng/mL) concentrations: MANF>GDNF>BDNF. GDNF was more selective at higher concentrations (25-50 ng/ml): GDNF>MANF>BDNF. Two domains in MANF of 39-AA and 109-AA respectively, and eight cysteines are conserved from C. elegans to man. MANF is encoded by a 4.3 Kb gene with 4 exons, and is located on the short arm of human chromosome 3. The secondary structure is dominated by alpha-helices (47%) and random coils (37%). Studies to determine the localization of MANF in the brains of rat, monkey, and man, as well as the receptor, signaling pathways, and biologically active peptide mimetics are in progress. The selective, neuroprotective effect of MANF for dopaminergic neurons suggests that it may be indicated for the treatment of Parkinson's disease.
J Mol Neurosci 2003 Apr
PMID:MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. 1279 11

We have previously demonstrated that profound and persistent neuropathic pain as displayed by mechanical and cold allodynia and thermal hyperalgesia can be produced by a lumbar 5 ventral root transection (L5 VRT) model in adult rats in which only the motor nerve fibers were injured without axotomy of sensory neurons. However, the underlying mechanisms remain to be determined. In this study, by examining its changes in expression and by inhibiting its functions using a neutralizing antibody, we have investigated whether nerve growth factor (NGF), a neurotrophic factor known to have a function in regulating nerve injury-induced pain, is involved in the development of neuropathic pain induced by L5 VRT. Motor nerve injury by L5 VRT resulted in a de novo expression of NGF mRNA in a subpopulation of small sensory neurons and pericellular satellite cells in ipsilateral L5 dorsal root ganglion. NGF protein expression was also increased by sensory neurons with various sizes and by keratinocytes in the target tissue ipsilateral skin. Systemic administration of NGF antiserum twice within 17 days markedly attenuated L5 VRT-induced mechanical allodynia but not the cold allodynia and thermal hyperalgesia. These findings suggest that NGF is an important pain mediator in the generation of mechanical sensitivity induced by L5 VRT.
Mol Cell Neurosci 2003 Jun
PMID:Lumbar 5 ventral root transection-induced upregulation of nerve growth factor in sensory neurons and their target tissues: a mechanism in neuropathic pain. 1281 56

The neurotrophic factor neurturin (NTN) is structurally related to the glial-derived neurotrophic factor (GDNF) and has been shown to prevent the degeneration of dopaminergic neurons both in vitro and in vivo. The preferred receptor for NTN is the GDNF family receptor alpha 2 (GFRalpha-2). To date, three protein-coding alternatively spliced GFRalpha-2 isoforms (GFRalpha-2a, GFRalpha-2b, GFRalpha-2c) have been identified in mammalian tissues. An accurate quantification of the expression levels is necessary when determining the contributions of these isoforms to NTN signaling in tissues. In this report, sequence independent real time RT-PCR is used to determine the expression levels of GFRalpha-2 isoforms at different developmental stages of the murine embryos, and in various adult tissues. In the adult murine brain, GFRalpha-2a was found to be the most abundant, GFRalpha-2c was slightly less and GFRalpha-2b was 10-fold lower. The testis did not appear to express significant levels of GFRalpha-2a, 2b or 2c, compared to the brain. A novel finding in this study is that in some tissues, including the adult brain, the expression levels of GFRalpha-2, as quantified by the amplification of the 3' sequences encoding the putative glycosyl-phosphatidylinositol anchor signal sequence, were significantly higher than the combined levels of GFRalpha-2a, GFRalpha-2b and GFRalpha-2c. This indicates the existence of yet to be identified forms of GFRalpha-2 in some tissues that may be of physiological significance.
Brain Res Mol Brain Res 2003 Jun 10
PMID:Real time PCR quantification of GFRalpha-2 alternatively spliced isoforms in murine brain and peripheral tissues. 1282 25

Neuropathic pain is a difficult clinical problem that is often refractory to medical management. Glial-derived neurotrophic factor (GDNF) administered intrathecally has been shown to prevent or reduce pain in an animal model of neuropathic pain, but cannot be delivered in the required doses to treat human pain. We have previously demonstrated that peripheral subcutaneous inoculation of a replication-incompetent herpes simplex virus (HSV)-based vector can be used to transduce neurons of the dorsal root ganglion. To examine whether HSV-mediated expression of GDNF could be used to ameliorate neuropathic pain, we constructed a replication-incompetent HSV vector expressing GDNF. Subcutaneous inoculation of the vector 1 week after spinal nerve ligation resulted in a continuous antiallodynic effect that was maintained for 3-4 weeks. Reinoculation of the vector reestablished the antiallodynic effect with a magnitude that was at least equivalent to the initial effect. Vector-mediated GDNF expression blocked the nonnoxious touch-induced increase in c-fos expression in dorsal horn characteristic of the painful state. Gene transfer to produce a trophic factor offers a novel approach to the treatment of neuropathic pain that may be appropriate for human therapy.
Mol Ther 2003 Sep
PMID:HSV-mediated gene transfer of the glial cell-derived neurotrophic factor provides an antiallodynic effect on neuropathic pain. 1294 9

The common neurotrophin receptor (p75NTR) is a member of the tumor necrosis factor receptor superfamily and binds the neurotrophins nerve growth factor, brain derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. P75NTR is expressed on developing motoneurons and is reexpressed on adult motoneurons under pathological conditions such as nerve trauma or neurodegeneration. Here we examined the regulation and function of p75NTR during regeneration after peripheral transection of the facial nerve of adult mice. Axotomy led to a strong increase in p75NTR immunoreactivity on the injured and regenerating facial motoneurons and on denervated Schwann cells. Cellular colocalization also revealed p75NTR immunoreactivity on neighboring blood vessels and cells in the injured nerve, but not on activated GFAP+ astrocytes or alphaMbeta2+ microglia and macrophages. To determine the function of this receptor we examined the effects of p75NTR deficiency on neuroglial activation, on the speed of axonal regeneration, and on neuronal survival after facial axotomy in two different transgenic mouse lines carrying targeted insertions exon 4 (p75e4-/-) or exon 3 (p75e3-/-) of the p75NTR gene. In both animal models absence of p75NTR led to a twofold, early increase in the number of CD3+. T-cells and in the microglial immunoreactivity for the alpha5beta1, alpha6beta1, and alphaMbeta2 integrins at day 4 in the facial nucleus and in the crushed facial motor nerve. No changes were observed in the number of reactive GFAP+ astrocytes or on late microglial and lymphocyte responses. The rate of axonal elongation in the crushed facial nerve, as well as neuronal survival, was found to be unaffected. Overall, the current study shows that the p75NTR receptor plays an important regulatory role in early neuroglial and immune activation.
Mol Cell Neurosci 2003 Oct
PMID:Regulation, cellular localization, and function of the p75 neurotrophin receptor (p75NTR) during the regeneration of facial motoneurons. 1457 55

Basic fibroblast growth factor (or FGF-2) has been shown to be a potent stimulator of retinal ganglion cell (RGC) axonal growth during development. Here we investigated if FGF-2 upregulation in adult RGCs promoted axon regrowth in vivo after acute optic nerve injury. Recombinant adeno-associated virus (AAV) was used to deliver the FGF-2 gene to adult RGCs providing a sustained source of this neurotrophic factor. FGF-2 gene transfer led to a 10-fold increase in the number of axons that extended past 0.5 mm from the lesion site compared to control nerves. Detection of AAV-mediated FGF-2 protein in injured RGC axons correlated with growth into the distal optic nerve. The response to FGF-2 upregulation was supported by our finding that FGF receptor-1 (FGFR-1) and heparan sulfate (HS), known to be essential for FGF-2 signaling, were expressed by adult rat RGCs. FGF-2 transgene expression led to only transient protection of injured RGCs. Thus the effect of this neurotrophic factor on axon extension could not be solely attributed to an increase in neuronal survival. Our data indicate that selective upregulation of FGF-2 in adult RGCs stimulates axon regrowth within the optic nerve, an environment that is highly inhibitory for regeneration. These results support the hypothesis that key factors involved in axon outgrowth during neural development may promote regeneration of adult injured neurons.
Mol Cell Neurosci 2003 Nov
PMID:Fibroblast growth factor-2 gene delivery stimulates axon growth by adult retinal ganglion cells after acute optic nerve injury. 1466 16

Neurturin, a member of the glial cell-derived neurotrophic factor familys of ligands, is important for development of many cranial parasympathetic ganglion neurons. We have investigated the sacral component of the parasympathetic nervous system in mice with gene deletions for neurturin or its preferred receptor, GFRalpha2. Disruption of neurturin signalling decreased cholinergic VIP innervation to the mucosa of the reproductive organs, but not to the smooth muscle layers of these organs or to the urinary bladder. Thus, neurturin and its receptor are involved in parasympathetic innervation of a select group of pelvic visceral tissues. In contrast, noradrenergic innervation was not affected by the gene ablations. The epithelium of reproductive organs from knockout animals was atrophied, indicating that cholinergic innervation may be important for the maintenance of normal structure. Cholinergic neurons express GFRalpha2 on their terminals and somata, indicating they can respond to neurotrophic support, and their somata are smaller when neurturin signalling is disrupted. Colocalisation studies showed that many peripheral glia express GFRalpha2 although its role in these cells is yet to be determined. Our results indicate that neurturin, acting through GFRalpha2, is essential for parasympathetic innervation of the mucosae of reproductive organs, as well as for maintenance of a broader group of sacral parasympathetic neurons.
Mol Cell Neurosci 2004 Feb
PMID:Neurturin signalling via GFRalpha2 is essential for innervation of glandular but not muscle targets of sacral parasympathetic ganglion neurons. 1501 45

Developing neurons encounter a panoply of extracellular signals as they differentiate. A major goal is to identify these extrinsic cues and define the mechanisms by which neurons simultaneously integrate stimulation by multiple factors yet initiate one specific biological response. Factors that are known to exert potent activities in the developing nervous system include the NGF family of neurotrophic factors, ciliary neurotrophic factor (CNTF), and pituitary adenylate cyclase-activating peptide (PACAP). Here we demonstrate that PACAP promotes the differentiation of nascent dorsal root ganglion (DRG) neurons in that it increases both the number of neural-marker-positive cells and axonogenesis without affecting the proliferation of neural progenitor cells. This response is mediated through the PAC1 receptor and requires MAP kinase activation. Moreover, we find that, in the absence of exogenously added PACAP, blockade of the PAC1 receptor inhibits neuronal differentiation. These data coupled with our finding that both PACAP and the PAC1 receptor are expressed during the peak period of neuronal differentiation in the DRG suggest that PACAP functions in vivo to promote the differentiation of nascent sensory neurons. Interestingly, we also demonstrate that the neurotrophic factors NT-3 and CNTF completely block the PACAP-induced neuronal differentiation. This points to the intricate integration of cellular signals by nascent neurons and, to our knowledge, is the first evidence for neurotrophic factor abrogation of a pathway regulated by G-protein-coupled receptors (GPCRs).
Mol Cell Neurosci 2004 Apr
PMID:PACAP promotes sensory neuron differentiation: blockade by neurotrophic factors. 1508 Aug 92


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