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

Nurr1 and NGFI-B are closely related orphan members of the steroid-thyroid hormone receptor family involved in immediate early responses to stimuli such as growth factors. In-situ hybridization in the developing and adult mouse and rat demonstrated Nurr1 mRNA in several regions during early central nervous system (CNS) development. Expression persisted through the pre- and postnatal periods and was also found in several areas in the adult CNS. Positive areas include the olfactory bulb, parts of the cortex, the hippocampal formation and substantia nigra where Nurr1 and tyrosine hydroxylase mRNAs were co-expressed. 6-Hydroxydopamine-induced degeneration of mesencephalic dopamine neurons led to a corresponding loss of Nurr1 mRNA, demonstrating a link between Nurr1 and dopaminergic neurons. NGFI-B mRNA was not found in the prenatal CNS but was highly expressed in the adult brain in many areas including the olfactory bulb, cortex, basal ganglia and hippocampus. The spatiotemporal distribution of Nurr1 and NGFI-B mRNAs suggests that these transcription factors are involved in the development and maturation of specific sets of CNS neurons. The experimental data imply that one of these functions may be to control gene regulatory events important for development and function of those neurons that degenerate in patients with Parkinson's disease.
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PMID:Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system. 888 41

Dopamine neurons of the substantia nigra and ventral tegmental area regulate movement and affective behavior and degenerate in Parkinson's disease. The orphan nuclear receptor Nurr1 was shown to be expressed in developing dopamine neurons before the appearance of known phenotypic markers for these cells. Mice lacking Nurr1 failed to generate midbrain dopaminergic neurons, were hypoactive, and died soon after birth. Nurr1 expression continued into adulthood, and brains of heterozygous animals, otherwise apparently healthy, contained reduced dopamine levels. These results suggest that putative Nurr1 ligands may be useful for treatment of Parkinson's disease and other disorders of midbrain dopamine circuitry.
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PMID:Dopamine neuron agenesis in Nurr1-deficient mice. 913 42

In the adult mammalian central nervous system lost nerve cells are not replaced and there is no regeneration of injured axons in white matter. Together, these two facts mean that there are no spontaneous reparative mechanisms in operation. Instead, the adult central nervous system copes with the risks of injuries and diseases by protective encapsulation in bone, by a multitude of neuroprotective mechanisms, and finally by the fact that many important functions are represented by a much larger number of neurons than minimally needed. The long life expectancy of a human being nevertheless means that the risk that the central nervous system is affected by disease, injury or other forms of insults for which it cannot fully compensate is relatively high. Experimentally, two strategies are being pursued in order to develop ways of minimizing various forms of CNS damage, namely neuroprotective and reparative strategies. Here we present a possible reparative intervention applicable to spinal cord injury based on multiple white-to-gray matter peripheral nerve bridge grafts and work based on the specific role of Nurr1 for dopamine neuron development, suggesting that development of ligands to transcription factor might be a new inroad to neuroprotective treatments in Parkinson's disease.
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PMID:On CNS repair and protection strategies: novel approaches with implications for spinal cord injury and Parkinson's disease. 965 46

Recent reports have revealed that Nurr1 (also known as NOT/TINUR/RNR-1/HZF-3), a member of the steroid/thyroid hormone nuclear receptor superfamily, is predominantly expressed in the midbrain; substantia nigra (SN) and ventral tegmental area (VTA). Nurr1 null mice are born lethal, lacking the midbrain dopamine (DA) neurons, suggesting that Nurr1 is essential for the development and differentiation of midbrain DA neurons. Human Nurr1 gene has been mapped on chromosome 2q22-23, which is reported to associate weakly with schizophrenia. We cloned and sequenced the human Nurr1 gene, which is approximately 8.3kb long, consisting of eight exons and seven introns. Comparisons of the human Nurr1 with the mouse Nurr1, mouse Nur77 and human NOR-1 revealed that their genomic structures were highly conserved. The 5'-flanking region of the human Nurr1 included three transcriptional regulatory elements, cAMP-response element (CRE), CArG-like element and Sp-1 site, which were surrounded by CpG island, and showed a strong homology with the mouse Nurr1. We performed a primer extension analysis using mRNA from HeLa S3 cells stimulated with phorbol 12-myristate 13-acetate (PMA), Ca2+ ionophore A23187 and cycloheximide (CHX) in order to induce the Nurr1 mRNA expression, and determined one transcription initiation site within CRE. The transient transfection assay indicates that the regulatory elements in the 5'-flanking region are robust for mitogen-induced expression of the human Nurr1. Further analysis of the polymorphism of the human Nurr1 gene may reveal the association with diseases characterized by changes of the DA system, such as Parkinson's disease and schizophrenia.
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PMID:Organization of the human orphan nuclear receptor Nurr1 gene. 1021 61

Nurr1 is a member of the nuclear receptor superfamily of transcription factors that is expressed predominantly in the central nervous system, including developing dopaminergic neurons. Recently, it was demonstrated that Nurr1 is critical for midbrain dopaminergic cell differentiation. In order to investigate a possible relation of Nurr1 with the pathogenesis of Parkinson's disease or other neuropsychiatric disorders, we have cloned and characterized the human Nurr1 gene. The gene exists as a single copy in the human genome and comprises eight exons spanning 8kb. We determined the complete nucleotide sequence and flanking regions of the gene. Potential regulatory regions included consensus binding sites for NF-kappaB, CREB, and Sp1. Isolation of human Nurr1 cDNAs from fetal brain suggested the presence of a new splicing variant of Nurr1 in the human brain.
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PMID:Molecular cloning of the human Nurr1 gene: characterization of the human gene and cDNAs. 1021 62

The implementation of neural stem cell lines as a source material for brain tissue transplants is currently limited by the ability to induce specific neurochemical phenotypes in these cells. Here, we show that coordinated induction of a ventral mesencephalic dopaminergic phenotype in an immortalized multipotent neural stem cell line can be achieved in vitro. This process requires both the overexpression of the nuclear receptor Nurr1 and factors derived from local type 1 astrocytes. Over 80% of cells obtained by this method demonstrate a phenotype indistinguishable from that of endogenous dopaminergic neurons. Moreover, this procedure yields an unlimited number of cells that can engraft in vivo and that may constitute a useful source material for neuronal replacement in Parkinson's disease.
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PMID:Induction of a midbrain dopaminergic phenotype in Nurr1-overexpressing neural stem cells by type 1 astrocytes. 1040 49

Nurr1, a member of the nuclear receptor superfamily of transcription factors, has been found to be essential for the development of ventral midbrain dopamine (DA)ergic neurons. To study the regional selectivity and phenotypic specificity of regulation by Nurr1 of the genesis of DAergic neurons, we examined DAergic, serotonin (5-HT)ergic, norepinephrine (NE)ergic, cholinergic, glutamate (GLU)ergic, and gamma-aminobutyric acid (GABA)ergic neurons in the brains of Nurr1-deficient mice by immunohistochemistry and biochemistry. We demonstrated that in homozygous Nurr1-deficient mice (Nurr1-/-), DAergic neurons were totally absent in substantia nigra and ventral tegmental area, but preserved in other regions including diencephalon and hypothalamus, olfactory bulb (OB). Levels of DA in Nurr1-/- mice were decreased by 98% in striatum (Str) and 65% in OB. NEergic neurons in locus ceruleus, 5-HTergic neurons in raphe nuclei, and cholinergic neurons in basal forebrain and other regions were not changed. A 30% reduction of NE was found in the Str of Nurr1-/- mice. The levels of GLU and GABA and the activity of choline acetyl transferase in the brains of Nurr1-/- mice were not significantly altered. Our results demonstrate a selective and specific deficit of DA and absence of DAergic neurons in the mesencephalic structures of Nurr1-deficient mice, which resembles the pattern similar to that seen in patients with Parkinson's disease (PD). This model may contribute to our understanding of the mechanisms influencing DAergic cell survival in PD.
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PMID:Selective agenesis of mesencephalic dopaminergic neurons in Nurr1-deficient mice. 1050 16

New data support a role for growth hormone secretagogue receptor agonists as rejuvenating agents. Two enzymes critical for the formation of beta-amyloid plaques in Alzheimer's disease have been identified. Estrogen receptor beta continues to emerge as a potential drug target. The orphan nuclear receptor Nurr1 appears to be a target for treatment of Parkinson's disease, and propargylamines are emerging as inhibitors of oxidative damage in neurons.
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PMID:The aging process: where are the drug opportunities? 1095 63

Various factors, including the orphan nuclear receptor Nurr1, have been implicated in dopamine biosynthesis, but many of the specific events involved in this process have to be determined. Using genetic manipulations in mice, the obligatory role for Nurr1 in dopamine (DA) biosynthesis has been documented; however, the mechanism remains unclear. DA biosynthetic enzymes, transporters and receptors are absent in the substantia nigra (SN) and the ventral tegmental area (VTA) of Nurr1-null neonates. The current study establishes that the loss of Nurr1 function does not affect the normal ventralization of neuroepithelial cells to the ventral midbrain, their differentiation into neurons, and their topographical pattern in the SN and VTA. Futhermore, the absence of Nurr1 does not affect the survival of these DA precursor cells in the ventral midbrain, as determined by quantitative analysis of cells, expressing the general neuronal nuclear marker (NeuN) and the TUNEL assay for apoptosis. These neurons express cholecystokinin (CCK), a co-transmitter of dopaminergic neurons in this area. The untranslated exon 1-2 of the Nurr1 gene, which remains intact after homologous recombination, revealed the presence of dopaminergic precursors in the ventral midbrain of the Nurr1-null mice. In addition, these neurons establish their nigrostriatal projections, as shown by axonal transport of a fluorescent tracer, DiI. These results provide evidence that Nurr1 is essential for terminal differentiation of the dopaminergic neurons in the ventral midbrain but does not affect the early steps of their neurogenesis, migration, survival and striatal projections. Our findings suggest that activation of Nurr1 might be therapeutically useful in Parkinson's disease.
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PMID:Nigrostriatal innervation is preserved in Nurr1-null mice, although dopaminergic neuron precursors are arrested from terminal differentiation. 1111 33

Neural progenitor cells potentially provide a limitless, on-demand source of cells for grafting into patients with Parkinson's disease (PD) if the signals needed to control their conversion into dopamine (DA) neurons could be identified. We have recently shown that cytokines which instruct cell division and differentiation within the hematopoeitic system may provide similar functions in the central nervous system. We have shown that mitotic progenitor cells can be isolated from embryonic rat mesencephalon and that these cells respond to a combination of interleukin-1, interleukin-11, leukemia inhibitory factor, and glial cell line-derived neurotrophic factor yielding a tyrosine hydroxylase-immunoreactive (THir) phenotype in 20-25% of total cells. In the present study, 24 clonal cell lines derived from single cells of mesencephalic proliferation spheres were examined for their response to the cytokine mixture. The clone yielding the highest percentage of THir neurons (98%) was selected for further study. This clone expressed several phenotypic characteristics of DA neurons and expression of Nurr1. The response to cytokines was stable for several passages and after cryopreservation for several months. When grafted into the striatum of DA-depleted rats, these cells attenuated rotational asymmetry to the same extent as freshly harvested embryonic DA neurons. These data demonstrate that mesencephalic progenitor cells can be clonally expanded in culture and differentiated in the presence of hematopoietic cytokines to yield enriched populations of DA neurons. When transplanted, these cells provide significant functional benefit in the rat model of PD.
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PMID:A clonal line of mesencephalic progenitor cells converted to dopamine neurons by hematopoietic cytokines: a source of cells for transplantation in Parkinson's disease. 1152 Jan 24


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