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)

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

Estrogen receptor beta (ERbeta) is expressed at high levels in both neurons and glial cells of the central nervous system. The development of ERbeta knockout (BERKO) mice has provided a model to study the function of this nuclear receptor in the brain. We have found that the brains of BERKO mice show several morphological abnormalities. There is a regional neuronal hypocellularity in the brain, with a severe neuronal deficit in the somatosensory cortex, especially layers II, III, IV, and V, and a remarkable proliferation of astroglial cells in the limbic system but not in the cortex. These abnormalities are evident as early as 2 mo of age in BERKO mice. As BERKO mice age, the neuronal deficit becomes more pronounced, and, by 2 yr of age, there is degeneration of neuronal cell bodies throughout the brain. This is particularly evident in the substantia nigra. We conclude that ERbeta is necessary for neuronal survival and speculate that this gene could have an important influence on the development of degenerative diseases of the central nervous system, such as Alzheimer's disease and Parkinson's disease, as well as those resulting from trauma and stroke in the brain.
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PMID:Morphological abnormalities in the brains of estrogen receptor beta knockout mice. 1122 19

Nurr1 is a member of the nuclear receptor superfamily of transcription factors that is highly expressed in midbrain dopaminergic (DA) neurons, the cells primarily lost in human Parkinson's disease (PD), and in Nurr1-null mice selective agenesis of midbrain DA neurons is found. To investigate possible correlation between the expression of Nurr1 gene and neurotoxin-induced cell death of DA neurons, a neural stem cell line (NSC, A3) and Nurr1-overexpressing NSC (A3.Nurr1) were exposed to DA neurotoxins 6-hydroxydopamine (6-OHDA) and methyl phenylpyridinium (MPP(+)). Although both neurotoxins were shown to induce cell death in A3 and A3.Nurr1 cells, patterns of cell deaths were different. A3.Nurr1 cells showed increased vulnerability to 6-OHDA cytotoxicity, but increased resistance to MPP(+)-induced cell death when compared to A3 cells. To investigate the differential vulnerability to neurotoxins by Nurr1 protein correlates with biochemical features that discriminate between apoptosis and necrosis, we carried out a nucleosomal DNA fragmentation assay and electron microscopy. While 6-OHDA treatment induced shrinkage of cytoplasmic membrane, condensation of nuclei and generation of apoptotic bodies in both cell lines, cells treated with MPP(+) showed mitochondrial swelling, indicating that 6-OHDA- but not MPP(+)-mediated cell death was apoptotic. These results suggest that DA neuronal cell death in response to 6-OHDA and MPP(+) may progress through separate signaling pathways differentially regulated by the Nurr1 protein. Our observations indicated that Nurr1 may play a role in the manifestation of DA neurotoxicity and that variations in Nurr1 expression might be a susceptibility factor for DA neurodegeneration in PD.
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PMID:Overexpression of midbrain-specific transcription factor Nurr1 modifies susceptibility of mouse neural stem cells to neurotoxins. 1240 63

NR4A2, encoding a member of nuclear receptor superfamily, is essential for the differentiation of the nigral dopaminergic neurons. To determine whether NR4A2 is a susceptibility gene for Parkinson disease, we carried out genetic analyses in 201 individuals affected with Parkinson disease and 221 age-matched unaffected controls. We identified two mutations in NR4A2 associated with Parkinson disease (-291Tdel and -245T-->G), which map to the first exon of NR4A2 and affect one allele in 10 of 107 individuals with familial Parkinson disease but not in any individuals with sporadic Parkinson disease (n = 94) or in unaffected controls (n = 221). The age at onset of disease and clinical features of these ten individuals were not different from those of individuals with typical Parkinson disease. The mutations resulted in a marked decrease in NR4A2 mRNA levels in transfected cell lines and in lymphocytes of affected individuals. Additionally, mutations in NR4A2 affect transcription of the gene encoding tyrosine hydroxylase. These data suggest that mutations in NR4A2 can cause dopaminergic dysfunction, associated with Parkinson disease.
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PMID:Mutations in NR4A2 associated with familial Parkinson disease. 1249 59

Regional differences in gene expression are critical to the proper development of specialized cell types in the nervous system. The ventral midbrain is the prominent source of dopaminergic neurons, which are affected in Parkinson's disease. We have recently identified a gene regulatory element that is specifically active in ventral midbrain neuroepithelium of developing embryos. This 204-bp transcriptional enhancer is conserved within the second intron of mammalian nestin genes and contains a putative binding site for a protein of the nuclear receptor family. Our present study shows, by mutagenesis and reporter gene assay in transgenic mice, that this site is essential for enhancer function in the developing midbrain. The characterization of regulatory sites and transcription factors with specific activity in the ventral midbrain provides insight into the molecular mechanisms by which neural progenitor cells become specified towards particular neuronal differentiation pathways.
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PMID:Mutation of a putative nuclear receptor binding site abolishes activity of the nestin midbrain enhancer. 1252 31

Neural stem cells are self-renewing cells capable of differentiating into all neural lineage cells in vivo and in vitro. In the present study, coordinated induction of midbrain dopaminergic phenotypes in an immortalized multipotent neural stem cell line can be achieved by both overexpression of nuclear receptor Nurr1, and fibroblast growth factor-8 (FGF-8), and sonic hedgehog (Shh) signals. Nurr1 overexpression induces neuronal differentiation and confers competence to respond to extrinsic signals such as Shh and FGF-8 that induce dopaminergic fate in a mouse neural stem cell line. Our findings suggest that immortalized NSCs can serve as an excellent model for understanding mechanisms that regulate specification of ventral midbrain DA neurons and as an unlimited source of DA progenitors for treating Parkinson disease patients by cell replacement.
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PMID:Sonic hedgehog and FGF8 collaborate to induce dopaminergic phenotypes in the Nurr1-overexpressing neural stem cell. 1276 35

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.
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PMID:NR4A2 and schizophrenia: lack of association in a Portuguese/Brazilian study. 1521 29


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