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)

Neuronal injury has been consistently found in A10 midbrain dopamine neurons in Parkinson's disease (PD). To assess changes in neurotransmitter-related gene transcription, in these neurons in PD, tyrosine hydroxylase (TH) mRNA expression was examined in the ventral tegmental area (VTA) of seven PD cases and seven control subjects, using in situ hybridization histochemistry (ISHH). In controls, TH mRNA expression was found in both melanised and non-melanised neurons in the VTA. Neither population expressed dopamine beta-hydroxylase (DBH). Of the melanised neurons, 99% were TH mRNA positive. The level of the TH mRNA signal (expressed as grain density per cell) was similar in the two populations (melanised: 0.129+/-0.004 (mean+/-S.E.M.), n=142 vs. non-melanised: 0.138+/-0.006, n=89, P>0.05, Student's t-Test). In PD cases there was no significant change in TH mRNA expression in melanised neurons (0.138+/-0.003, n=196), and the proportion of positively labeled melanised neurons was 98%. However, non-melanised neurons showed significantly higher TH mRNA (0.163+/-0.006, n=87) than non-melanised neurons in control subjects (P<0.005) and melanised neurons in the PD cases (P<0.0005). This up-regulation of TH mRNA expression in non-melanised neurons may suggest the existence of a compensatory mechanism at presynaptic level.
Brain Res Mol Brain Res 2000 Jun 23
PMID:Up-regulation of tyrosine hydroxylase mRNA in a sub-population of A10 dopamine neurons in Parkinson's disease. 1092 42

NMDA receptor activation during status epilepticus (SE) has previously been shown to be required for epileptogenesis as well as the persistent upregulation of serum response factor (SRF) in the in vivo pilocarpine model of epilepsy. SRF is established as a regulator of the FosB gene which expresses FosB and DeltaFosB components of the AP-1 transcription factor complex. Therefore we investigated whether DeltaFosB expression and AP-1 DNA binding were also persistently elevated in pilocarpine-treated rats which chronically displayed spontaneous seizures. Using hippocampal nuclear extracts, DeltaFosB expression and AP-1 DNA binding were significantly elevated for up to one year in the epileptic animals. The expression of other fos and jun proteins was not persistently altered in epilepsy. Neuronal upregulation of DeltaFosB was correlated with regions of the brain that were involved in seizure generation and propagation. The increase in AP-1 DNA binding was shown to be dependent on NMDA receptor activation during SE. Hippocampal DeltaFosB immunostaining was seen predominately in the neuronal nuclei as opposed to other cell types. The data indicate that recurrent seizures which persistently occur in this model were not responsible for the increased DeltaFosB expression. Chronic DeltaFosB expression in epilepsy may be playing a role in the altered expression of other genes in this model and may be involved in some of the neuronal plasticity changes associated with epileptogenesis.
Brain Res Mol Brain Res 2000 Jun 23
PMID:Chronic DeltaFosB expression and increased AP-1 transcription factor binding are associated with the long term plasticity changes in epilepsy. 1092 51

Neuronal muscarinic (M(2)) receptors inhibit release of acetylcholine from the vagus nerves. Hyperreactivity in antigen-challenged guinea pigs is due to blockade of these M(2) autoreceptors by eosinophil major basic protein (MBP) increasing the release of acetylcholine. In vivo, substance P-induced hyperactivity is vagally mediated. Because substance P induces eosinophil degranulation, we tested whether substance P-induced hyperreactivity is mediated by release of MBP and neuronal M(2) receptor dysfunction. Pathogen-free guinea pigs were anesthetized and ventilated. Thirty minutes after intravenous administration of [Sar(9),Met(O(2))(11)]- substance P, guinea pigs were hyperreactive to vagal stimulation and M(2) receptors were dysfunctional. The depletion of inflammatory cells with cyclophosphamide or the administration of an MBP antibody or a neurokinin-1 (NK(1)) receptor antagonist (SR-140333) all prevented substance P-induced M(2) dysfunction and hyperreactivity. Intravenous heparin acutely reversed M(2) receptor dysfunction and hyperreactivity. Thus substance P releases MBP from eosinophils resident in the lungs by stimulating NK(1) receptors. Substance P-induced hyperreactivity is mediated by blockade of inhibitory neuronal M(2) receptors by MBP, resulting in increased release of acetylcholine.
Am J Physiol Lung Cell Mol Physiol 2000 Sep
PMID:Substance P-induced airway hyperreactivity is mediated by neuronal M(2) receptor dysfunction. 1095 22

Neuronal survival during the developmental period of naturally occurring cell death is mediated through a successful competition for limiting concentrations of neurotrophic factors, and the deprived neurons will die. New results show that induced death through the p75 neurotrophin receptor (p75(NTR)), a member of the p55TNF/Fas family of cell death receptors, may also influence survival during development. We find that eliminating p75(NTR) or neurotrophin 4 (NT4) in mice leads to a marked attenuation of apoptosis during the programmed cell death period of the trigeminal ganglion neurons, suggesting that NT4 can induce the death of these neurons through the p75(NTR). These in vivo findings were reproduced in primary cell cultures, where NT4 was found to induce death in a p75(NTR)-dependent pathway. Analysis of p75 deficient and wild-type cells revealed two separate cell death pathways, a p75(NTR)- and caspase-3-independent pathway activated by trophic factor deprivation, and a p75(NTR)- and caspase-3-dependent pathway initiated by NT4. Crossing in the NT4 null alleles in brain-derived neurotrophic factor (BDNF) null mutant mice led to a rescue of a large proportion of BDNF-dependent neurons from excessive cell death, indicating that trophic factor deprivation is not sufficient for the death of many neurons and that additional death inducing signals might be required. Our results suggest that NT4 competitively signals survival and death of sensory neurons through trkB and p75(NTR), respectively.
Mol Cell Neurosci 2000 Sep
PMID:Attenuation of a caspase-3 dependent cell death in NT4- and p75-deficient embryonic sensory neurons. 1099 52

Neuronal ceroid lipofuscinoses (NCL) form a distinct group of storage diseases where the normal development of the central nervous system is interrupted and neurons of the neocortex begin to degenerate. Mutations in genes encoding three lysosomal enzymes are the causes for three early-onset forms of NCLs: palmitoyl-protein thioesterase 1 (PPT1) is deficient in human infantile NCL, tripeptidyl peptidase 1 (TTP1) in late-infantile NCL, and cathepsin D in congenital ovine NCL. We wanted to compare the developmental expression profiles of these enzymes in rat brain. In conclusion, the PPT1 expression pattern differed from the two other lysosomal enzymes implicated in NCL diseases, thus suggesting a distinctive role for PPT1 in brain development.
Mol Genet Metab
PMID:Developmental changes in the expression of neuronal ceroid lipofuscinoses-linked proteins. 1100 10

Neuronal cytoskeletal elements such as neurofilaments, F-actin, and microtubules are actively translocated by an as yet unidentified mechanism. This report describes a novel interaction between neurofilaments and microtubule motor proteins that mediates the translocation of neurofilaments along microtubules in vitro. Native neurofilaments purified from spinal cord are transported along microtubules at rates of 100-1000 nm/s to both plus and minus ends. This motion requires ATP and is partially inhibited by vanadate, consistent with the activity of neurofilament-bound molecular motors. Motility is in part mediated by the dynein/dynactin motor complex and several kinesin-like proteins. This reconstituted motile system suggests how slow net movement of cytoskeletal polymers may be achieved by alternating activities of fast microtubule motors.
Mol Biol Cell 2000 Oct
PMID:Bidirectional translocation of neurofilaments along microtubules mediated in part by dynein/dynactin. 1102 51

Neuronal glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) proteins mediate the transcriptional effects of circulating glucocorticoids. These receptors bind the same DNA response element, yet mediate quite different cellular functions. The present study tests the hypothesis that acute and chronic stress, which cause increases in glucocorticoids sufficient to bind the GR, will regulate expression of the GR and MR genes in the hippocampal formation. Analysis of MR gene transcription using an intronic MR probe revealed a transient 50% decrease in MR hnRNA in CA1, CA3 and dentate gyrus at 60-120 min post-stress, consistent with glucocorticoid down-regulation of the MR gene. However, no changes were seen in full-length MR mRNA at any post-stress time point. In contrast, GR hnRNA was not affected by acute stress, but GR mRNA was decreased 120 min post stress in all hippocampal subregions. Chronic stress exposure down-regulated GR mRNA in CA3 only; effects were first evident 7 days post stress and persisted for the entire stress time-course (28 days). There was no evidence for down-regulation of GR hnRNA or MR hnRNA/mRNA at any point in the chronic stress regimen. The transient decrease in MR hnRNA in the absence of mRNA changes suggests increased MR mRNA stability. In contrast, acute stress decreases the availability of GR mRNA without demonstrably affecting transcription, suggesting reduced GR mRNA stability. The results suggest that acute stress alters GR mRNA expression by largely post-transcriptional mechanisms. However, elevations in basal corticosterone secretion seen following chronic stress are not sufficient to markedly down-regulate GR/MR expression in a long-term fashion.
Brain Res Mol Brain Res 2000 Sep 15
PMID:Stress regulation of adrenocorticosteroid receptor gene transcription and mRNA expression in rat hippocampus: time-course analysis. 1103 47

Neuronal loss and neuritic/cytoskeletal lesions (synaptic disconnection and proliferation of dystrophic neurites) represent major dementia-associated abnormalities in Alzheimer's disease (AD). This study examined the role of oxidative stress as a factor contributing to both the cell death and neuritic degeneration cascades in AD. Primary neuron cultures were treated with H2O2 (9-90 microM) or desferrioxamine (2-25 microM) for 24 h and then analyzed for viability, mitochondrial mass, mitochondrial function, and pro-apoptosis and sprouting gene expression. H2O2 treatment causes free-radical injury and desferrioxamine causes hypoxia-type injury without free radical generation. The H2O2-treated cells exhibited sustained viability but neurite retraction, impaired mitochondrial function, increased levels of the pro-apoptosis gene product CD95/Fas, reduced expression of N2J1-immunoreactive neuronal thread protein and synaptophysin, and reduced distribution of mitochondria in neuritic processes. Desferrioxamine treatment resulted in dose-dependent neuronal loss associated with impaired mitochondrial function, proliferation of neurites, and reduced expression of GAP-43, which has a role in path-finding during neurite outgrowth. The results suggest that oxidative stress can cause neurodegeneration associated with enhanced susceptibility to apoptosis due to activation of pro-apoptosis genes, neurite retraction (synaptic disconnection), and impaired transport of mitochondria to cell processes where they are likely required for synaptic function. In contrast, hypoxia-type injury causes neuronal loss with proliferation of neurites (sprouting), impaired mitochondrial function, and reduced expression of molecules required to form and maintain synaptic connections. Since similar abnormalities occur in AD, both oxidative stress and hypoxic injury can contribute to AD neurodegeneration.
Cell Mol Life Sci 2000 Sep
PMID:Oxidative stress and hypoxia-like injury cause Alzheimer-type molecular abnormalities in central nervous system neurons. 1107 24

The CXC chemokine receptor CXCR4 was the first molecule identified as a coreceptor working in conjunction with CD4 to mediate cellular entry for the human immunodeficiency virus (HIV-1). Since that original discovery, 11 other seven-mtransmembrane domain molecules, many of which are chemokine receptors, have been shown to facilitate HIV entry into cells. These include CCR5, CCR3, CCR2, CCR1, CCR8, CX3CR1, STRL33 (BONZO), GPR15 (BOB), GPR1, US28, and APJ. In studies done by this and other labs, CCR3, CCR5, and CXCR4 have been identified in CNS microglia and several laboratories, including ours, have shown that CXCR4 is expressed in neurons. Neuronal expression of CCR2, CCR3, and CCR5 has been less consistent. We performed a semiquantitative immunohistochemical analysis of the expression of CCR2, CCR3, CCR5, and CXCR4 in 23 regions of the brain and in two sections of the spinal cord. Hippocampal neurons were positive for CCR2, CCR3, and CXCR4, but not for CCR5. In other regions of the brain, neurons, and glial cells reacted with anti-CCR2, anti-CCR3, and anti-CXCR4 antibodies, whereas only glial cells (primarily microglia) were positive for CCR5. The areas of highest expression, however, seem to be subcortical regions and the limbic system. The limbic system plays a key role in memory, and the presence of CXCR4-which can bind the viral envelope protein gp120-min a subset of neurons from this system may play a role in the development of HIV-related dementia.
Exp Mol Pathol 2000 Dec
PMID:Immunohistochemical analysis of CCR2, CCR3, CCR5, and CXCR4 in the human brain: potential mechanisms for HIV dementia. 1111 60

Ca2+-binding proteins containing EF-hands are important constituents of intracellular signaling pathways. Recently, three new members of the Neuronal Calcium Sensor subgroup have been cloned in humans. Calsenilin interacts with presenilins, DREAM is a calcium-regulated transcriptional repressor and KChIP3 binds and modulates A-type potassium channels. Here we describe the mouse full-length cDNA and the genomic locus, demonstrating that the three proteins are encoded by the same unique gene. Various mechanisms contribute to the coding potential of this locus. These include alternate translation starts in the first exon and alternative splicing yielding transcripts lacking the EF-hand domains. In situ hybridization, RT-PCR, and Northern blotting reveal nervous system-restricted expression largely coinciding with the distribution of the Kv4.2 alpha-subunit of potassium channels. The presence of transcripts in early embryonic stages suggests roles for the protein also during development.
Mol Cell Neurosci 2001 Jan
PMID:Mouse DREAM/calsenilin/KChIP3: gene structure, coding potential, and expression. 1116 65


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