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)

The mesencephalic dopaminergic (mesDA) system is involved in many brain functions including motor control and motivated behaviour, and is of clinical importance because of its implication in psychiatric disorders and Parkinson's disease. Nurr1, a member of the nuclear hormone receptor superfamily of transcription factors, is essential for establishing the dopaminergic phenotype, because expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, requires Nurr1. In addition, Nurr1 plays an important role in the maintenance of mesDA neurons. Neonatal Nurr1 knockout mice lack expression of the dopamine transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and l-aromatic amino acid decarboxylase (AADC) in addition to TH specifically in mesDA neurons. It is unclear whether the lack of expression of these dopaminergic markers is caused by a maintenance defect or whether the induction of these markers depends on Nurr1 expression. To address this problem, the expression of DAT, VMAT2 and AADC was analysed at embryonic day 12.5 and 14.5. Here we demonstrate that induction of VMAT2 and DAT specifically in mesDA neurons requires Nurr1 expression, whereas AADC expression in mesDA neurons is induced independently of Nurr1 function.
 ...
PMID:Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons. 1462 7

We investigated the dopaminergic (DA) neuronal degeneration in animals subjected to systemic treatment of rotenone via subcutaneous delivery. Behavioral observations revealed a hypokinetic period in rats sacrificed at 3 and 5 days, and dystonic episodes in animals sacrificed at 8 days. Less than 20% of the total number of animals given rotenone depicted brain lesions after 8 days of treatment, as demonstrated by a significant loss of DA fibers in the striatum, but not of DA nigral neurons. Tyrosine hydroxylase-negative striatal territories were characterized by post-synaptic toxicity as demonstrated by a decreased number of interneurons labeled for choline acetyltransferase, NADPH-diaphorase, parvalbumin, and projection neurons labeled for calbindin and nerve growth factor inducible-B (NGFI-B). Post-synaptic neurodegeneration was demonstrated further by abundant striatal staining for Fluoro-Jade. Decrease in the nuclear orphan receptor Nurr1 expression was the only significant change observed at the level of the substantia nigra. Autopsy reports confirmed that animals suffered from severe digestion problems. These data suggest that hypokinesia observed between 3 and 5 days is the result of general health problems rather than a specific motor deficit associated to Parkinson's disease (PD) symptoms. Overall, the effects of rotenone toxicity are widespread, and subcutaneous administration of this toxin does not provide the neuropathological and behavioral basis for a relevant and reliable PD model.
 ...
PMID:Rotenone induces non-specific central nervous system and systemic toxicity. 1476 96

Parkinson's disease (PD) is a common neurodegenerative disorder in humans with wide variability in the age of disease onset. Although the disease has been thought previously to occur sporadically in most patients, there is increasing evidence of a genetic contribution to the disorder. Recently, a polymorphic variant within intron 6 of the Nurr1 gene was reported to be associated with sporadic and familial PD. In an effort to identify susceptibility genes for PD, we have collected 783 PD patients from 372 families and 397 healthy controls from 217 families. PD patients and healthy controls were genotyped for the intron 6 insertion polymorphism by BseRI restriction endonuclease digestion. No significant difference in either homozygosity or heterozygosity for the 7048G7049 (IVS6 1361 +16insG) polymorphism was detected in the PD patient cohort as compared with the panel of healthy controls. Moreover, direct sequencing of exon 1 of the Nurr1 gene in PD patients failed to detect either of the two recently reported Nurr1 mutations identified in a small subset of a PD patient cohort. Taken together, these data suggest that genetic alteration at the Nurr1 locus is not a significant risk factor for the development of Parkinson's disease in our large sample of familial PD patients.
 ...
PMID:Evaluation of the role of Nurr1 in a large sample of familial Parkinson's disease. 1519 2

The present study investigates the association of mutations in the nuclear receptor NR4A2 in schizophrenic patients. The human Nur-related receptor 1, NR4A2, is an orphan nuclear receptor that can be constitutively active as a transcription factor and for which no natural ligand has yet been identified. Alone or with retinoid X receptor, RXR, NR4A2 influences the expression of several genes important for human brain development and regulation. In the absence of Nurr1 (the mouse homologue to human NR4A2), ventral mesencephalic dopaminergic mouse neurons evidence severe developmental failure, a condition that is lethal soon after birth. Nurr1 involvement in the dopaminergic system makes it a good candidate for study in neuropsychiatric disorders such as schizophrenia and Parkinson disease. Evidence by others support this hypothesis (1) mapping of the NR4A2 gene to chromosome 2q22-23, a region with suggestive linkage to schizophrenia and (2) identification of mutations in patients with schizophrenia (c.366-369delTAC, c.308A > G, c.-469delG), manic depression (c.289A > G), and familial Parkinson's disease (c.-291delT, c.-245T > G). To further extend these observations, we searched for all these mutations in 176 Caucasian Portuguese and 82 Caucasian Brazilian subjects with lifetime diagnosis of schizophrenia. The study failed to identify any of the described mutations in patients or controls. Nevertheless, these negative results do not exclude altered expression of nuclear receptors in schizophrenia or the presence of other mutations.
 ...
PMID:NR4A2 and schizophrenia: lack of association in a Portuguese/Brazilian study. 1521 29

For cell replacement therapy of neurodegenerative diseases such as Parkinson's disease (PD), methods for efficiently generating midbrain dopaminergic (DA) neurons from embryonic stem (ES) cells have been investigated. Two aspects of DA neuron generation are considered: genetic modification and manipulation of culture conditions. A transcription factor known as critical for development of DA neurons, Nurr1, was introduced into ES cells to see how they facilitate the generation of DA neurons from ES cells. Also, two culture procedures, the 5-stage method and stromal cell-derived inducing activity (SDIA) method, were used for ES cell differentiation. Using the 5-stage method, we and others previously demonstrated that Nurr1-overexpressing ES cells, under treatment of signaling molecules such as SHH and FGF8 followed by treatment of ascorbic acid, can differentiate into DA neurons with a high efficiency (> 60% of TH+/Tuj1+ neurons). Furthermore, using the SDIA method with treatment of signaling molecules, we found that Nurr1-overexpressing ES cells can differentiate to DA neurons with the highest efficiency ever reported (approximately 90% of TH+/Tuj1+ neurons). Importantly, our semi-quantitative and real-time PCR analyses demonstrate that all known DA marker genes (e.g., TH, AADC and DAT) were up-regulated in Nurr1- overexpressing ES cells when compared to the na ve ES cells. These cells produced increased dopamine compared to na ve D3 cells after differentiation. In the in vivo context after transplantation, the genetically modified ES cells also showed the highly increased dopaminergic neuronal phenotypes. Thus, the combination of genetic engineering and appropriate culture conditions provides a useful tool to generate a good cell source from ES cells for cell replacement therapy of degenerative diseases such as PD.
 ...
PMID:Efficient induction of dopaminergic neurons from embryonic stem cells for application to Parkinson's disease. 1562 19

With a view toward improving the neural bioavailability of administered dopaminergic compounds, including dopamine, synthetic efforts have been directed toward enhancing the brain bioavailability of these compounds by accessing cellular sugar transport systems with stereoselective dopaminergic drugs. While synthesis and chemistry of the resultant class of compounds has recently been described in US Patent No. 6,548,484, the associated biologic properties have not previously been reported. One member of this new class, IPX-750, is a pro-drug dopamine-gluconamine designed to retain stereospecificity of binding at: glucose transporters (GLUT 1/GLUT 3 and intestinal Na/glucose co-transporters SGLT1), dopamine transporter (DAT); and, dopaminergic receptors of the D1/D2 families. Designed to be cleavable by tissue amidases, results reported here show that intact IPX-750 pro-drug retains dopaminergic agonist binding and biologic activities both in vitro and in vivo. IPX-750, like dopamine, exhibited predominant D5/D1 binding specificity with lower binding activity at D2. As expected, binding was highly stereo-specific, ie, IPX-760, a benzamide differing in just a hydrogen atom and keto oxygen from IPX-750, bound with 6-fold lower activity at D5. In cell culture, activation resulted from binding of IPX-750 at D1 or D5 in transfected cells was measured by increased intracellular cAMP. Interestingly, considering prior reported in vitro toxicity of dopamine oxidized and metabolic product dopamine, no evidence of in vitro toxicity was observed at up to 72 hrs in cell cultures at the EC50 of IPX-750 for increasing intracellular cAMP. IPX-750 was evaluated in the Parkinson's disease animal models, including MPTP mouse model, the 6-hydroxydopamine (6-OHDA) rat model and the Nurr1(+/-) knockout mouse model. In MPTP-lesioned and Nurr1+/- knockout mice, IPX-750 significantly increased Rota-rod time. In 6-OHDA-lesioned rats, IPX-750 significantly decreased apomorphine (APO)-induced rotation. Worthy of note, after cessation of IPX-750 treatments the anti-parkinsonian activity in MPTP-lesioned and Nurr1+/- mice required about 2 weeks to washout, suggesting a possible biologic reservoir of drug. In addition, after eight weeks of twice daily administration of 20 mg/kg IPX-750, mice did not show statistical difference in the total number of TH-positive neurons in substantia nigra (SN). These combined results suggest (i) that stereo-specific glycoconjugation may be an effective method to improve penetrability of drugs through the blood brain barrier; (ii) treatment with bioavailable IPX-750 in vitro did not show evidence for neurotoxicity; and, (iii) IPX-750 possesses dopaminergic properties and exerts anti-parkinsonian effects in three different PD rodent models, suggesting therapeutic potential for this new class of drugs in treating dopamine deficiency diseases.
 ...
PMID:Dopaminergic properties and experimental anti-parkinsonian effects of IPX750 in rodent models of Parkinson disease. 1525 66

Parkinson's disease (PD) is characterised by the death of dopaminergic neurons of the substantia nigra. As Nurr1 seems to regulate the development and maintenance of these neurons, we evaluated its potential role in Parkinson's disease using genetic methods. We genotyped two polymorphisms and screened a case-control sample for the presence/absence of two mutations recently described in exon 1. Our results failed to replicate the association initially observed and none of the mutations were present in our familial Parkinson's disease cases. These observations suggest that this gene is unlikely to play a major effect in French familial Parkinson disease.
 ...
PMID:Assessment of Nurr1 nucleotide variations in familial Parkinson's disease. 1527 33

We performed sequence analysis of all the exons and exon-intron boundaries in familial and young-onset Parkinson's disease (PD) in an Asian cohort. None of the patients carried any pathogenic mutations in the Nurr1 gene. We demonstrated a 5 to 10% prevalence of the intron 7 +33 C-->T variant among Malay and Indian PD and healthy controls, suggesting that this variant, which was previously described only in 1 Chinese patient, was not a silent mutation but a common polymorphic variant in some ethnic races.
 ...
PMID:Nurr1 mutational screen in Parkinson's disease. 1539 59

Stem cells are currently considered as alternative cell resources for restorative transplantation strategies in Parkinson's disease. However, the mechanisms that induce differentiation of a stem cell toward the dopaminergic phenotype are still partly unknown thus hampering the production of dopaminergic neurons from stem cells. In the past, FGF-20 has been found to promote the survival of ventral mesencephalic (VM) dopaminergic (DA) neurons in culture. We hereby provide evidence that FGF-20, a growth factor of the FGF family, is expressed in the adult and 6-OHDA-lesioned striatum and substantia nigra, but is not expressed by VM glia or DA neurons, suggesting that FGF-20 may work on DA neurons in a paracrine- or target-derived manner. We also found that co-culture of Nurr1-NSCs with Schwann cells overexpressing FGF-20 induced the acquisition of a neuronal morphology by the NSCs and the expression of tyrosine hydroxylase (TH) as assessed by immunocytochemistry, cell ELISA, and Western blot analysis. RT-PCR showed, that both, Schwann cells and Nurr1-NSCs (differentiated or not), expressed the FGF-1 receptor suggesting that both direct and indirect actions of FGF-20 are possible. We show that differentiated Nurr1 cells retained both neuronal morphology and TH expression after transplantation into the striatum of 6-OHDA-lesioned postnatal or adult rats, but that neuritogenesis was only observed after postnatal grafts. Thus, our results suggest that FGF-20 promotes the differentiation of Nurr1-NSCs into TH-positive neurons and that additional factors are required for the efficient differentiation of DA neurons in the adult brain.
 ...
PMID:Fibroblast growth factor-20 promotes the differentiation of Nurr1-overexpressing neural stem cells into tyrosine hydroxylase-positive neurons. 1547 54

The Nurr1 gene, which codes for a transcriptional factor in the nuclear receptor superfamily, plays an important role in the development of the mesencephalic dopaminergic (DAergic) system. To study the age-dependent effects of Nurr1 expression in maintaining mature nigrostriatal DAergic neuronal function, we examined motor behaviors, determined nigrostriatal dopamine (DA) levels and the number of nigral DAergic neurons, and measured the expression of several DAergic neuron-associated genes in heterozygous Nurr1-deficient (Nurr1+/-) and wild-type mice of different ages. In contrast to the same-aged, wild-type mice, old Nurr1+/- mice (>15 months) had a significant decrease in both rotarod performance and locomotor activities, suggesting a motor impairment that is analogous to parkinsonian deficit. Furthermore, the abnormal motor behaviors in old Nurr1+/- mice were associated with decreased DA levels in the striatum, decreased number of DAergic neurons in the nigra, and reduced expression of Nurr1 and DA transporter in the nigra. Our data indicate that Nurr1 plays an important role in the functional maintenance and survival of nigral DAergic neurons and suggest that the Nurr1+/- mouse is a useful animal model to study the pathogenesis of Parkinson disease (PD) and to explore disease-modifying strategies.
 ...
PMID:Age-dependent dopaminergic dysfunction in Nurr1 knockout mice. 1558 22


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>