Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using an antibody that recognizes the products of all known members of the fos family of immediate early genes, it was demonstrated that destruction of the nigrostriatal pathway by 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle produces a prolonged (>3 months) elevation of Fos-like immunoreactivity in the striatum. Using retrograde tract tracing techniques, we have previously shown that this increase in Fos-like immunoreactivity is located predominantly in striatal neurons that project to the globus pallidus. In the present study, Western blots were performed on nuclear extracts from the intact and denervated striatum of 6-OHDA-lesioned rats to determine the nature of Fos-immunoreactive protein(s) responsible for this increase. Approximately 6 weeks after the 6-OHDA lesion, expression of two Fos-related antigens with apparent molecular masses of 43 and 45 kDa was enhanced in the denervated striatum. Chronic haloperidol administration also selectively elevated expression of these Fos-related antigens, suggesting that their induction after dopaminergic denervation is mediated by reduced activation of D2-like dopamine receptors. Western blot immunostaining using an antibody which recognizes the N-terminus of FosB indicated that the 43 and 45 kDa Fos-related antigens induced by dopaminergic denervation and chronic haloperidol administration may be related to a truncated form of FosB known as deltaFosB. Consistent with this proposal, retrograde tracing experiments confirmed that deltaFosB-like immunoreactivity in the deafferented striatum was located predominantly in striatopallidal neurons. Gel shift experiments demonstrated that elevated AP-1 binding activity in denervated striata contained FosB-like protein(s), suggesting that enhanced deltaFosB levels may mediate some of the effects of prolonged dopamine depletion on AP-1-regulated genes in striatopallidal neurons. In contrast, chronic administration of the D1-like receptor agonist CY 208243 to 6-OHDA-lesioned rats dramatically enhanced deltaFosB-like immunoreactivity in striatal neurons projecting to the substantia nigra. Western blot immunostaining revealed that deltaFosB and, to a lesser extent, FosB are elevated by chronic D1-like agonist administration. Both the quantitative reverse transcriptase-polymerase chain reaction and the ribonuclease protection assay demonstrated that deltafosB mRNA levels were substantially enhanced in the denervated striatum by chronic D1-like agonist administration. Lastly, we examined the effects of chronic administration ofD1-like and D2-like dopamine receptor agonists on striatal deltaFosB expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson's disease. In monkeys rendered Parkinsonian by MPTP, there was a modest increase in deltaFosB-like protein(s), while the development of dyskinesia produced by chronic D1-like agonist administration was accompanied by large increases in DeltaFosB-like protein(s). In contrast, administration of the long-acting D2-like agonist cabergoline, which alleviated Parkinsonian symptoms without producing dyskinesia reduced deltaFosB levels to near normal. Taken together, these results demonstrate that chronic alterations in dopaminergic neurotransmission produce a persistent elevation of deltaFosB-like protein(s) in both the rodent and primate striatum.
 ...
PMID:Chronic alterations in dopaminergic neurotransmission produce a persistent elevation of deltaFosB-like protein(s) in both the rodent and primate striatum. 871 7

Dopaminergic modulation of the DNA binding activity of AP-1, Sp1, CREB and AP-2 transcription factors was examined in rat striatal nuclear extracts by gel shift assay. AP-1 binding was selectively increased in the striatum following depletion of dopamine by 6-hydroxydopamine-induced lesion of the nigrostriatal pathway or after reserpine treatment. The D1 agonist SKF 38393 dose-dependently increased AP-1 binding; this effect was significantly increased in reserpine-treated rats and even more markedly enhanced in denervated striatum. The D2/D3 agonist quinpirole, administered alone, did not affect striatal activator protein-1 binding; in combination, quinpirole and SKF 38393 acted synergistically in normal and reserpine-treated rats but not in 6-hydroxydopamine-lesioned rats, suggesting that mechanisms underlying D1-D2/D3 interactions are altered after dopamine denervation. Most, but not all, of the changes in AP-1 binding activity observed in this study are consistent with changes in levels of Fos/Jun family proteins observed after similar treatments. These results support the hypothesis that D1 receptor stimulation activates striatonigral neurons and modulates expression of AP-1-related genes in these neurons, while D2 receptor stimulation mediates tonic inhibition of AP-1 expression and activity in the striatopallidal neurons. Moreover, the findings provide evidence that the loss of dopaminergic input to the striatum, as occurs in Parkinson's disease, induces long-lasting alterations in the regulation of striatal gene expression which may contribute to the disease's progress.
 ...
PMID:Dopaminergic regulation of AP-1 transcription factor DNA binding activity in rat striatum. 895 71

Parkinson's disease (PD) is characterized by the relatively selective and progressive loss of dopaminergic neurons in the substantia nigra. During the early stages of PD, there are marked compensatory changes in the dopaminergic system, although little is known of how these responses are orchestrated. Since the induction of cellular immediate-early genes (cIEG) has been linked to adaptive responses in the nervous system, we examined their expression in the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of PD. MPTP elicited an induction of c-fos, fosB, Delta-fosB and c-jun mRNAs in the striatum that persisted for 24 h. There was a parallel increase in AP-1-like DNA binding activity for up to 7 days post-treatment. At 7 days, AP-1 complexes were specifically supershifted with antisera to FosB and JunD. Immunoblotting of MPTP-treated striata with a FosB-specific antiserum revealed elevated levels of approximately 35 and approximately 46 kDa cross-reactive proteins. Only the 35 kDa protein was increased at 7 days. Thus, the persistent AP-1 complex seen in the MPTP-treated striatum is composed of JunD and a 35 kDa FosB-related protein, possibly Delta-FosB. In situ hybridization revealed elevated expression of fosB and Delta-fosB in the MPTP-treated brain. Expression of both transcripts was highest in ventral striatum, nucleus accumbens and other terminal fields of the mesolimbic system, such as the olfactory tubercle and Islands of Calleja. Thus, the increased fosB expression accompanying MPTP treatment was predominantly associated with dopaminergic pathways. Since FosB was expressed in both vulnerable and spared neuronal populations, we suggest that Delta-FosB-JunD heterodimers play a role in the adaptive response to MPTP neurotoxicity.
 ...
PMID:MPTP-Parkinsonism is accompanied by persistent expression of a delta-FosB-like protein in dopaminergic pathways. 947 80

Drugs and certain environmental toxins may be responsible for the pathogenesis of Parkinson's disease. We have used paraquat as a model toxin for this study since paraquat has been shown to make its way to the nerve terminals and cause cell death of dopamine neurons by oxidative injury. We have shown by the electrophoretic mobility shift assay that paraquat, together with low concentrations of chelated iron (Fe++/DETAPAC), induced the activation of transcription factor AP-1 binding activity to DNA. Under similar conditions we also found by both a DNA laddering assay procedure and by terminal deoxynucleotidyl transferase assay (TUNEL assay) that paraquat also induces apoptotic cell death. Interestingly, both apoptotic cell death and AP-1/DNA binding activity induced by paraquat were blocked by cyclohexamide and genistein, indicating that both the AP-1/DNA binding activation and apoptosis induced by paraquat are closely related. Moreover, cells were also protected from paraquat toxicity in the presence of antioxidant defense enzymes SOD and catalase. The results support the hypothesis that oxidative stress may be contributing to the apoptotic cell death of dopaminergic neurons, leading to the manifestation of Parkinson's disease. Since paraquat was an important herbicide in the mid 20th Century, our results have the important implication that exposure to environmental toxins such as paraquat may induce Parkinson's disease.
 ...
PMID:Paraquat induced activation of transcription factor AP-1 and apoptosis in PC12 cells. 1019 31

Inclusions containing ubiquitin-protein aggregates appear in neurons of patients with neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. The relationship between inclusion production and cell viability is not understood. To address this issue, we investigated the response of an established mouse neuronal cell line and of embryonic rat mesencephalic cultures to inhibition of the ubiquitin/proteasome pathway. Two proteasome inhibitors, a peptidyl aldehyde and an epoxy ketone, which cause accumulation of ubiquitinated proteins, were found to enhance expression of stress-inducible genes, including HSP70i and the polyubiquitin genes UbB and UbC. Under these conditions, mRNA and protein levels of the inducible form of cyclooxygenase (COX-2) were upregulated together with its product, PGE(2), a proinflammatory prostaglandin. Proteasomal inhibition also led to stabilization of COX-2 as ubiquitin conjugates, suggesting that the ubiquitin/proteasome pathway contributes to the regulation of COX-2 protein levels. Treatment with antioxidants known to inhibit NFkappaB and AP-1 transcriptional activation failed to abrogate COX-2 upregulation. Instead, these inhibitors exacerbated the stress response by potentiating HSP70i levels while eliciting a decrease in PGE(2) production. These findings suggest that the accumulation of ubiquitinated proteins resulting from proteasome inhibition in neuronal cells is associated with a proinflammatory response that may be an important contributor to neurodegeneration.
 ...
PMID:Proteasome inhibition in neuronal cells induces a proinflammatory response manifested by upregulation of cyclooxygenase-2, its accumulation as ubiquitin conjugates, and production of the prostaglandin PGE(2). 1066 14

High nonphysiological doses of l-dopa are administered to Parkinson's disease (PD) patients, to replenish the depleted dopamine (DA). A large portion of the administered L-dopa and the newly formed DA undergoes methylation by reacting with S-adenosyl-L-methionine (SAM). In the process SAM, as well as L-dopa and DA, is utilized and great demands are placed on the transmethylation system. In this study we investigated whether L-dopa increases the transmethylation process by inducing methionine adenosyl transferase (MAT), the enzyme that produces SAM, and catechol-O-methyl transferase (COMT), the enzyme that transfers the methyl group from SAM to L-dopa and DA. Swiss Webster mice were injected with L-dopa, four times/day, for 1 to 16 days. Brain DA, 3-O-methyldopa (3-OMD), SAM, S-adenosylhomocysteine (SAH), MAT, and COMT were measured following a 24-h withdrawal period. An increase of 264% of brain DA occurred at days 2 and 3 after which it tapered to about 164% of control. The brain level of 3-OMD increased to 870% of the control. SAM was increased by 44% after the sixth day and SAH level was about double after the second day. After day 3, MAT activity was increased by about 35%. Western blot analysis showed that MAT is more clearly characterized in 10% mercaptoethanol reducing buffer in which 31.5-, 38- (beta), and 48-kDa (alpha1/alpha2) subunits were distinctly revealed. The induction of the 38-kDa and, more prominently, the 48-kDa subunits of MAT and the potential transactivator proteins of MAT, c-Jun/AP-1, was evident by day 6. The 31.5-kDa subunit was downregulated. COMT was detected as 24.7-, 30-, and 47.5-kDa bands in the brain, consistent with the membrane-bound COMT I (MB-COMT) and the dimeric COMT II. The 24.7- and the 30-kDa MB-COMT bands were induced in the brain by day 6 and peaked on day 9. The highlight of the study is the fact that L-dopa induces the enzymes MAT and COMT. In addition, the downturn in brain DA after the sixth day coincides with the increase in SAM and the 48-kDa MAT protein. Thus, during PD treatment with L-dopa the induction of MAT and COMT is likely to occur and in turn increase the methylation and reduction of L-dopa and DA that may help cause the tolerance or the wearing-off effect developed to L-dopa.
 ...
PMID:L-dopa upregulates the expression and activities of methionine adenosyl transferase and catechol-O-methyltransferase. 1152 Jan 27

A possible source for transplantable neurons in Parkinson's disease are adult olfactory bulb (OB) dopamine (DA) progenitors that originate in the anterior subventricular zone and reach the OB through the rostral migratory stream. We used adult transgenic mice expressing a lacZ reporter directed by an 8.9 kb tyrosine hydroxylase (TH) promoter to investigate the course of DAergic differentiation. Parallel transgene and intrinsic TH mRNA expression occurred during migration of DA interneurons through the mitral and superficial granule cell layers before these cells reached their final periglomerular position. Differential transgene and calcium-calmodulin-dependent protein kinase IV expression distinguished two nonoverlapping populations of interneurons. Transgenic mice carrying a TH8.9kb/lacZ construct with a mutant AP-1 site demonstrated that this element confers OB DA-specific TH gene regulation. These results indicate that DA phenotypic determination is specific to a subset of mobile OB progenitors.
 ...
PMID:Phenotypic differentiation during migration of dopaminergic progenitor cells to the olfactory bulb. 1160 39

We investigated the transcriptional events and signaling pathways involved in the induction of heme oxygenase-1 (HO-1) by dieldrin, an environmental risk factor of Parkinson's disease, in a dopaminergic neuronal cells (SN4741). Dieldrin exposure caused dose-dependent and time-dependent induction of heme oxygenase activity and HO-1 protein expression. Deletional and mutational analyses showed that the 5' distal enhancers, E1 and E2, mediate dieldrin-induced HO-1 gene transcription, and the AP-1 DNA binding sites in the E2 enhancer are critical for E2-mediated HO-1 gene activation. Furthermore, both the p38 and JNK mitogen-activated protein kinase pathways are utilized for HO-1 transcriptional activation by dieldrin. HO-1 inhibitor, ZnPP IX reduced the expression of HO-1 but enhanced the cytotoxicity induced by dieldrin.
 ...
PMID:Heme oxygenase-1 induction by dieldrin in dopaminergic cells. 1577 Jan 61

Poly(ADP-ribosyl) ation is a reversible post-translational protein modification implicated in the regulation of a number of biological functions. Whereas an 18 member superfamily of poly(ADP-ribose) polymerase (PARP) enzymes synthesize poly(ADP-ribose) (PAR), a single protein, PAR glycohydrolase (PARG) is responsible for the catabolism of the polymer. PARP-1 accounts for more than 90% of the poly(ADP-ribosyl)ating capacity of the cells. PARP-1 activated by DNA breaks cleaves NAD(+) into nicotinamide and ADP-ribose and uses the latter to synthesize long branching PAR polymers covalently attached to acceptor proteins including histones, DNA repair enzymes, transcription factors and PARP-1. Whereas activation of PARP-1 by mild genotoxic stimuli may facilitate DNA repair and cell survival, irreparable DNA damage triggers apoptotic or necrotic cell death. In apoptosis, early PARP activation may assist the apoptotic cascade [e.g. by stabilizing p53, by mediating the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus or by inhibiting early activation of DNases]. In most severe oxidative stress situations, excessive DNA damage causes over activation of PARP-1, which incapacitates the apoptotic machinery and switches the mode of cell death from apoptosis to necrosis. Besides serving as a cytotoxic mediator, PARP-1 is also involved in transcriptional regulation, most notably in the NF kappaB and AP-1 driven expression of inflammatory mediators. Pharmacological inhibition or genetic ablation of PARP-1 provided remarkable protection from tissue injury in various oxidative stress-related disease models ranging from stroke, diabetes, diabetic endothelial dysfunction, myocardial ischemia-reperfusion, shock, Parkinson's disease, arthritis, colitis to dermatitis and uveitis. These beneficial effects are attributed to inhibition of the PARP-1 mediated suicidal pathway and to reduced expression of inflammatory cytokines and other mediators (e.g. inducible nitric oxide synthase).
 ...
PMID:Structure and function of poly(ADP-ribose) polymerase-1: role in oxidative stress-related pathologies. 1602 17

While isolating morphine-dependence-related genes with differential display, we cloned a novel human gene, zinc finger CCHC-type and RNA-binding motif 1 (ZCRB1, alias MADP-1) encoding a nuclear protein (217 residues). The ZCRB1 gene consists of eight exons and seven introns. It is mapped to 12q12, which is within a locus reported for Parkinson disease (M. Funayama et al., Ann. Neurol. 51 (2002) 296-301). The 5'-flanking region contains an enhancer core motif and binding sites for AP-1, AP-2, and LF-A1. ZCRB1 is characterized by an RNA-binding motif and a CCHC zinc finger motif. The latter overlaps the C..C...GH....C core nucleocapsid motif. ZCRB1 is conserved from zebrafish to human and shares homology with cold-inducible RNA-binding protein. Transfection assay showed that ZCRB1 is located in the nucleoplasm, but outside the nucleolus. ZCRB1 gene expression was stimulated by morphine, inhibited by 30-36 degrees C, and up-regulated by 39 degrees C incubation in SH-SY5Y neural cells. Zcrb1 gene expression is highest in the heart and testes, lower in the cerebellum, and lowest in the liver in mice. ZCRB1 mRNA expression is specifically elevated in hepatocarcinoma HepG2 cells. These data provide new clues for further understanding of morphine dependence, heat shock, and hepatocarcinoma.
 ...
PMID:Isolation, expression, and characterization of the human ZCRB1 gene mapped to 12q12. 1695 69


1 2 3 Next >>