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)

Glutamate toxicity has been involved in the pathophysiology of a large variety of neurodegenerative disorders. Tau Protein is a micro-tubule-associated protein that promotes microtubule polymerization and stabilization. Phosphorylated tau protein accumulates in paired helical neurofilaments, the major constituent of neurofibrillary tangles observed in the brain of patients suffering from Alzheimer disease (AD). In this study, using confocal laser microscopy and immunoblot analysis, we report that acute (500 mu M for 15 min) or chronic (20 mu M for 16 h) N-methyl-D-aspartate (NMDA) neuronal toxicities modify the immunoreactivity of phosphorylated tau. Neuronal degeneration produced by N-methyl-D-aspartate is associated with an augmented immunolabeling of phosphorylated tau proteins at serine 202 (AT8 antibody) as observed in paired helical neurofilaments. This finding could help to determine the cellular mechanisms at the origin of neuronal degeneration associated with modifications of phosphorylated tau immunoreactivity produced by receptor-mediated extracellular signals.
Mol Chem Neuropathol 1996 Apr
PMID:Modifications of neuronal phosphorylated tau immunoreactivity induced by NMDA toxicity. 914 12

Functional recovery from peripheral nerve injury and repair depends on a multitude of factors, both intrinsic and extrinsic to neurons. Neuronal survival after axotomy is a prerequisite for regeneration and is facilitated by an array of trophic factors from multiple sources, including neurotrophins, neuropoietic cytokines, insulin-like growth factors (IGFs), and glial-cell-line-derived neurotrophic factors (GDNFs). Axotomized neurons must switch from a transmitting mode to a growth mode and express growth-associated proteins, such as GAP-43, tubulin, and actin, as well as an array of novel neuropeptides and cytokines, all of which have the potential to promote axonal regeneration. Axonal sprouts must reach the distal nerve stump at a time when its growth support is optimal. Schwann cells in the distal stump undergo proliferation and phenotypical changes to prepare the local environment to be favorable for axonal regeneration. Schwann cells play an indispensable role in promoting regeneration by increasing their synthesis of surface cell adhesion molecules (CAMs), such as N-CAM, Ng-CAM/L1, N-cadherin, and L2/HNK-1, by elaborating basement membrane that contains many extracellular matrix proteins, such as laminin, fibronectin, and tenascin, and by producing many neurotrophic factors and their receptors. However, the growth support provided by the distal nerve stump and the capacity of the axotomized neurons to regenerate axons may not be sustained indefinitely. Axonal regenerations may be facilitated by new strategies that enhance the growth potential of neurons and optimize the growth support of the distal nerve stump in combination with prompt nerve repair.
Mol Neurobiol
PMID:The cellular and molecular basis of peripheral nerve regeneration. 917 Jan 1

Extensive programmed cell death (PCD) occurs in the developing nervous system. Neuronal death occurs, at least in part, because neurons are produced in excess during development and compete with each other for the limited amounts of the survival-promoting trophic factors secreted by target tissues. Neuronal death is apoptotic and utilizes components that are conserved in other PCD pathways. In this review, we discuss the mechanism of trophic factor-dependent neuronal cell death by focusing on the pathway of nerve growth factor (NGF) deprivation-induced sympathetic neuronal death. We describe the biochemical and genetic events that occur in NGF-deprived sympathetic neurons undergoing PCD. Participation of the Bcl-2 family of proteins and the interleukin-1beta-converting enzyme family of proteases (caspases) in this and other models of neuronal death is also examined. The order and importance of these components during NGF deprivation-induced sympathetic neuronal death are discussed.
Mol Pharmacol 1997 Jun
PMID:Programmed cell death in neurons: focus on the pathway of nerve growth factor deprivation-induced death of sympathetic neurons. 918 55

Neuronal nitric oxide is hypothesized to participate in regulation of autonomic function by decreasing sympathetic output to the periphery. This hypothesis predicts that gene expression of neuronal nitric oxide synthase is increased during states of heightened sympathetic activity. To test the hypothesis, we measured gene expression in the spontaneously hypertensive rat (SHR), a genetic model of hypertension in which sympathetic activity is correlated with increasing pressure. SHRs and two strains of control rats (Wistar-Kyoto [WKY] and Sprague-Dawley [SD]) at 4 weeks (pre-hypertensive) and 14 weeks (established hypertension) of age were used to measure gene expression in hypothalamus, dorsal pons, dorsal medulla, rostral ventrolateral medulla, and caudal ventrolateral medulla. Semi-quantitative reverse transcription-polymerase chain reactions and in situ hybridization were used to measure changes in neuronal nitric oxide synthase mRNA. No significant differences were found in any of the areas studied among the three strains of rats in the 4-week rats. At 14 weeks significant increases in gene expression were found in the hypothalamus (73% compared to WKYs, 104% compared to SDs), dorsal medulla (31% and 45%), and caudal ventrolateral medulla (24% and 27%) of SHRs. In situ hybridization revealed that neurons expressing the synthase gene in the hypothalamus were found primarily in the paraventricular (both parvo- and magnocellular divisions) and supraoptic nuclei. These data show that gene expression of neuronal nitric oxide synthase is increased in central autonomic centers in animals with increased sympathetic activity and they support the hypothesis that nitric oxide plays an important role in maintenance of homeostatic balance through modulation of sympathetic activity.
Brain Res Mol Brain Res 1997 Sep
PMID:Increased gene expression of neuronal nitric oxide synthase in brain of adult spontaneously hypertensive rats. 933 26

Vasoactive intestinal peptide (VIP) has been shown to be a potent promoter of neuronal survival. Pituitary adenylate cyclase-activating peptide (PACAP), a homologous peptide, shares activity and receptor molecules with VIP. The neuroprotective effects of VIP have been shown to be mediated via astroglial-derived molecules. Utilizing a battery of antisense oligodeoxynucleotides directed against the multiple cloned VIP-preferring (VIP receptors 1 and 2) or PACAP-preferring receptors (six splice variants derived from the same gene transcript), the authors have demonstrated the existence of a specific PACAP receptor splice variant (PACAP4 or hop2) on astrocytes as well as a VIP type2 receptor. The identification of the receptors was achieved by incubation of the cells in the presence of the specific antisense oligodeoxynucleotide followed by radiolabeled VIP binding and displacement. Polymerase chain reaction (PCR) coupled to direct sequencing identified the expression of the PACAP4-hop2 receptor splice variant in astrocytes. Neuronal survival assays were conducted in mixed neuronal-glial cultures derived from newborn rat cerebral cortex. When these cultures were exposed to the battery of the antisense oligodeoxynucleotides, in serum-free media, only the PACAP-specific ones (e.g., hop2-specific) had an effect in decreasing neuronal cell counts. Thus, the VIP neuronal survival effect is mediated, at least in part, via a specific PACAP receptor (containing a unique insertion of 27 amino acids--the hop2 cassette). These data indicate that a hop2-like PACAP/VIP receptor is the receptor that mediates neurotropism.
J Mol Neurosci 1997 Dec
PMID:Identification of VIP/PACAP receptors on rat astrocytes using antisense oligodeoxynucleotides. 948 22

Autosomal dominant cerebellar ataxia with progressive macular degeneration is caused by a CAG/glutamine repeat expansion in the SCA7 gene/protein. Neuronal intranuclear inclusions were detected in the brain of an early onset SCA7 case with the 1C2 antibody directed against an expanded polyglutamine domain. Nuclear inclusions were most frequent in the inferior olivary complex, a site of severe neuronal loss in SCA7. They were also observed in other brain regions, including the cerebral cortex, not considered to be affected in the disease. Using confocal microscopy we showed that some inclusions were ubiquitinated, but to varying degrees, ranging from <1% in the cerebral cortex to 60% in the inferior olive. In addition, we also observed cytoplasmic staining using the 1C2 antibody, particularly in the supramarginal gyrus, the hippocampus, the thalamus, the lateral geniculate body and the pontine nuclei. These data confirm that the presence of intranuclear inclusions in neurons is a common characteristic of disorders caused by CAG/polyglutamine expansions, but unlike what has been reported for Huntington's disease, SCA1 and SCA3/MJD, in SCA7 the inclusions were not restricted to the sites of severe neuronal loss.
Hum Mol Genet 1998 May
PMID:Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. 953 97

Programmed cell death (PCD) (apoptosis) is implicated in the neuronal cell death of Alzheimer's disease (AD). We investigated expression of amyloid precursor protein (APP) and amyloid precursor-like protein 2 (APLP2) during trophic factor deprivation-induced PCD of neuronally differentiated PC12 cells. Neuronal PC12 cells underwent PCD within two days following withdrawal of nerve growth factor (NGF) from the culture medium. Total APP mRNA levels increased gradually after 24 h, reaching levels 250% higher than those in control cells at 48 h after NGF withdrawal, and total APLP2 mRNA levels also increased similarly at 48 h. Analysis of the three major APP mRNA isoforms APP695, APP751, and APP770 by reverse transcription polymerase chain reaction showed a substantial increase in the proportion of APP770 at 48 h after NGF withdrawal. Basic fibroblast growth factor, which prevented the appearance of PCD after NGF withdrawal, inhibited the increases in APP and APLP2 mRNA levels as well as the increase in the proportion of APP770. Cellular holoprotein levels of total APP, APP containing the Kunitz protease inhibitor domain, and APLP2 also increased by approximately 60%, 100%, and 30%, respectively, at 48 h after NGF withdrawal. These data indicate that in neuronal PC12 cells undergoing PCD following trophic factor withdrawal, the syntheses of both APP and APLP2 are upregulated, and the alternative splicing of the APP gene is modified. This implies a linkage between APP and APLP2 expression and neuronal PCD.
Brain Res Mol Brain Res 1998 May
PMID:Increased expression of amyloid precursor protein and amyloid precursor-like protein 2 during trophic factor withdrawal-induced death of neuronal PC12 cells. 960 12

Neuronal bungarotoxin (NBT) is a highly selective, slowly reversible, competitive antagonist of the alpha3beta2 neuronal nicotinic receptor. Contributions to NBT sensitivity are made by both the alpha3 and beta2 subunits. We used a chimeric alpha subunit to demonstrate that the entire alpha3 contribution lies within sequence segment 84-215. Construction and analysis of a series of mutant alpha3 subunits identified seven amino acid residues (Thr143, Tyr184, Lys185, His186, Ile188, Gln198, Ser203) within this region that contribute to NBT sensitivity. Changing Thr143 to lysine, as in alpha2, resulted in a approximately 1000-fold loss of NBT sensitivity. The effect on NBT sensitivity of changing each of the other six residues ranged from 1.8- to 40.5-fold. More extensive mutagenesis demonstrated that Thr143 serves as part of the consensus sequence for glycosylation at N141, and it is this glycosylation that is the determinant of NBT sensitivity. Only serine could substitute for threonine to maintain full NBT sensitivity, and changing Asn141 to alanine resulted in a approximately 300-fold loss of NBT sensitivity. The chimera alpha2-181-alpha3, containing all identified determinants except the glycosylation site, formed receptors insensitive to 300 nM NBT. Installation of threonine to complete the glycosylation consensus site in this chimera conferred NBT sensitivity only 10-fold less than that of wild-type alpha3beta2. These seven determinants of NBT sensitivity are located in close proximity to a series of conserved residues that are common features of all nicotinic receptor binding sites.
Mol Pharmacol 1998 Jun
PMID:Glycosylation within the cysteine loop and six residues near conserved Cys192/Cys193 are determinants of neuronal bungarotoxin sensitivity on the neuronal nicotinic receptor alpha3 subunit. 961 16

1. Neuronal differentiation depends on crosstalk between genetic program and environmental cues. In this study we tried to dissect this complex interplay by culturing neurons from fetal rat brain cortices in a chemically defined, neuron-specific, medium and on different substrata, either artificial (poly-D-lysine) or natural. 2. Among the extracellular matrix compounds used in this study, two (collagen I and fibronectin) allowed only a weak attachment of cortical neurons to the substratum, while the others (collagen IV, laminin, and basal lamina from Engelbreth-Holm-Swarm sarcoma) allowed both firm attachment and moderate to extensive neurite outgrowth from neuronal cell bodies. 3. By using synapsin I gene expression as a parameter of neuronal differentiation, we found that neurite outgrowth and neuronal differentiation are not linearly linked. Synapsin I gene expression, in fact, was maximal in neurons cultured on laminin, while the fastest neuritic outgrowth was recorded in cultures on poly-D-lysine. 4. The data presented in this paper are consistent with the hypothesis that the extracellular matrix plays an active role in modulating the differentiative program of neurons.
Cell Mol Neurobiol 1998 Aug
PMID:Modulation of synapsin I gene expression in rat cortical neurons by extracellular matrix. 961 92

Neuronal nicotinic acetylcholine receptors (nAChRs) present in the central nervous system (CNS), are multimeric proteins constituted of two different subunits, alpha and beta, with different subtype arrangements and different pharmacological and functional properties. By in situ hybridization, we studied the distribution of the mRNA for the alpha4 subunit of nAChRs in brains of human 25-week old normal and fragile X fetuses. A strong hybridization signal was detected throughout the thalamus, cortex, pyramidal layer of the Ammon's horn, and the granular layer of the dentate gyrus. Several other areas including the claustrum, caudate nucleus, putamen, globus pallidus, subthalamic nucleus, subiculum, entorhinal cortex, and Purkinje cell layer displayed a low to moderate radiosignal. With few exceptions, our data in the human brain agree those previously reported in the rat. Also, our data indicate that the alpha4 subunit mRNA is produced early in the development, in the more differentiated cells, and in a site-specific manner. Additionally, the alpha4 mRNA is produced in the brain of fragile X fetuses with the same pattern and same intensity than in the normal fetal brain suggesting that alpha4 subunit mRNA production is not altered in the fragile X syndrome. High levels of alpha4 subunit mRNA in human fetal brain support the hypothesis of a morphogenic role of nAChRs during the early CNS development.
Brain Res Mol Brain Res 1998 Jul 15
PMID:Distribution of mRNA for the alpha4 subunit of the nicotinic acetylcholine receptor in the human fetal brain. 968 7


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