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)

Cell transplantation therapy using dopaminergic neurons derived from embryonic stem (ES) cells for the treatment of Parkinson's disease has been proposed as one of the major applications for stem cell-based therapy. However, the low collection efficiency of neurons from a culture dish and the rejection of cells after transplantation are expected to limit their future clinical applications. To overcome these problems, we examined the induction of neurogenesis of ES cells under free-floating conditions and microencapsulation of the obtained cell aggregates into an agarose hydrogel. Cell aggregates from ES cells were cultured in various media under the free-floating condition. Immunohistochemical staining for tyrosine hydroxylase (TH) and RT-PCR analyses for TH and Nurr1 showed that dopaminergic neurons were induced in ES cell aggregates cultured in a 1:2 mixture of conditioned medium of PA6 stromal cells and Glasgow minimum essential medium (GMEM) after 16 days in culture. The cell aggregates could be collected and were encased within agarose microcapsules without loss of dopaminergic neurons. The cell aggregates with/without microencapsulation were maintained in CM/GMEM for an additional period. KCl stimulation assays were done at day 23, 30, 37, 44, 51, and 58 to examine dopamine release. Dopamine release abilities were well maintained during 58 days of observation. Amounts of dopamine release from encapsulated cell aggregates were slightly higher than those of unencapsulated cell aggregates from day 16 to 58. Although efficacy for immunoisolation of the agarose microcapsules still remains for future in vivo studies, microencapsulation did not adversely affect viability and functions of the dopamine releasing ES cell progeny.
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PMID:Induction dopamine releasing cells from mouse embryonic stem cells and their long-term culture. 1639 22

Midbrain dopamine (DA) neurons play a central role in the regulation of voluntary movement, and their degeneration is associated with Parkinson's disease. Cell replacement therapies, and in particular embryonic stem (ES) cell-derived DA neurons, offer a potential therapeutic venue for Parkinson's disease. We sought to identify genes that can potentiate maturation of ES cell cultures to the midbrain DA neuron phenotype. A number of transcription factors have been implicated in the development of midbrain DA neurons by expression analyses and loss-of-function knockout mouse studies, including Nurr1, Pitx3, Lmx1b, Engrailed-1, and Engrailed-2. However, none of these factors appear sufficient alone to induce the mature midbrain DA neuron phenotype in ES cell cultures in vitro, suggesting a more complex regulatory network. Here we show that Nurr1 and Pitx3 cooperatively promote terminal maturation to the midbrain DA neuron phenotype in murine and human ES cell cultures.
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PMID:Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype. 1647 36

Multiple genes have been now identified as causing Parkinson's disease (PD). In 2003, two mutations were identified in exon 1 of the Nurr1 gene in 10 of 107 individuals with familial PD. To date, investigators have only focused on screening for these known mutations of the Nurr1 gene. All individuals were recruited from two Parkinson's disease clinics in Canada. Following PCR amplification of each exon of the Nurr1 gene, samples underwent denaturing high-performance liquid chromatography (DHPLC) analysis. Ten individuals also underwent direct sequencing as well as any samples where variants were identified. The Nurr1 gene was evaluated for 202 PD individuals, 37% of whom had at least one relative with PD and 100 control non-PD individuals. Using DHPLC and direct sequencing, we did not detect any sequence variants in exon 1. Variants in amplicon 6 were seen and direct sequencing confirmed a known NI6P polymorphism in intron 6. Novel polymorphisms were also identified in exon 3 and intron 5. A novel mutation was identified in exon 3 in one nonfamilial PD individual. This heterozygous C-to-G transversion resulted in a serine-to-cysteine substitution and was not identified in any of the other 602 chromosomes screened. Mutations in the Nurr1 gene in our large cohort of familial and sporadic PD individuals are rare. The novel mutation in exon 3 is predicted to affect phosphorylation and functional studies to assess this are underway. This is the first coding mutation identified in the Nurr1 gene for Parkinson's disease.
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PMID:Translated mutation in the Nurr1 gene as a cause for Parkinson's disease. 1653 45

We present a simple method for neural cell fate specification directly from mouse embryonic stem cells (ES cells) in serum-free conditions in the absence of embryoid body formation. Dissociated ES cells were cultured in serum-free media supplemented with vitamin B12 and heparin, but without any expensive cytokines. After 14 days in culture, beta-tubulin type III (TuJ1) and tyrosine hydroxylase (TH)-positive colonies were detected by immunocytochemical examinations. In addition, specific gene analyses by RT-PCR demonstrated expression of an early central nerve system, mature neuron, and midbrain dopaminergic neuron-specific molecules (i.e., nestin, middle molecular mass neurofilament protein, Nurr1, and TH, respectively). Dopamine was also detected in the culture media by reverse-phase HPLC analysis. These facts indicate that addition of vitamin B12/heparin to serum-free culture media induced neurons from ES cells, which included cells that released dopamine. Other supplements, such as putrescine, biotin, and Fe2+, could not induce neurons from ES cells by themselves, but produced synergistic effects with vitamin B12/heparin. The rate of TuJ1+/TH+ colony formation was increased threefold and the amounts of dopamine released increased 1.5-fold by the addition of a mixture of putrescine, biotin, and Fe2+ to vitamin B12/heparin culture media. Our method is a simple tool to differentiate ES cells to dopaminergic neurons for the preparation of dopamine-releasing cells for the cell transplantation therapy of Parkinson's disease. In addition, this method can facilitate the discovery of soluble factors and genes that can aid in the induction of the ES cell to its neural fate.
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PMID:One-step induction of neurons from mouse embryonic stem cells in serum-free media containing vitamin B12 and heparin. 1671 47

Tissue engineering is a prerequisite for cell replacement as therapeutic strategy for degenerative diseases, such as Parkinson's disease. In the present study, we investigated regional identity of mesencephalic neural progenitors and characterized their development toward ventral mesencephalic dopaminergic neurons. We show that neural progenitors from ventral and dorsal mouse embryonic day 12 mesencephalon exhibit regional identity in vitro. Treatment of ventral midbrain dissociated neurospheres with transforming growth factor beta (TGF-beta) increased the number of Nurr1- and tyrosine hydroxylase (TH)-immunoreactive cells, which can be further increased when the spheres are treated with TGF-beta in combination with sonic hedgehog (Shh) and fibroblast growth factor 8 (FGF8). TGF-beta differentiation signaling is TGF-beta receptor-mediated, involving the Smad pathway, as well as the p38 mitogen-activated protein kinase pathway. In vivo, TGF-beta2/TGF-beta3 double-knockout mouse embryos revealed significantly reduced numbers of TH labeled cells in ventral mesencephalon but not in locus coeruleus. TH reduction in Tgfbeta2(-/-)/Tgfbeta3(+/-) was higher than in Tgf-beta2(+/-)/Tgf-beta3(-/-). Most importantly, TGF-beta may ectopically induce TH-immunopositive cells in dorsal mesencephalon in vitro, in a Shh- and FGF8-independent manner. Together, the results clearly demonstrate that TGF-beta2 and TGF-beta3 are essential signals for differentiation of midbrain progenitors toward neuronal fate and dopaminergic phenotype.
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PMID:Transforming growth factor beta is required for differentiation of mouse mesencephalic progenitors into dopaminergic neurons in vitro and in vivo: ectopic induction in dorsal mesencephalon. 1674 Dec 29

We describe a method of generating an enriched population of NCAM-positive cells from a human teratocarcinoma cell line (NTera2/D1) and their differentiation into midbrain dopaminergic neurons in the absence of the caudalizing factor retinoic acid (RA). NTera2 cells were induced to form embryoid bodies and then to generate nestin-positive cells on treatment with serum-free defined medium supplemented with neurotrophic factors. We enriched the neuroprogenitor population by magnetic sorting of the nestin-positive cells using the antibody to neural cell adhesion molecule (NCAM). These cells were expanded by exposing them to the signaling molecule sonic hedgehog (SHH) in conjunction with fibroblast growth factor-8 (FGF-8). The predifferentiated cells when analyzed by RT-PCR showed expression of dopaminergic markers such as Nurr1, Engrailed-1, aromatic amino decarboxylase (AADC), VMAT2, tyrosine hydroxylase (TH), and dopamine transporter (DAT). These cells also stained positively for protein markers such as nestin, NCAM, MAP-2, and TH. We further demonstrated that when transplanted into the brain of Parkinsonian rats, these neuroprogenitor cells did not form tumors but differentiated into dopaminergic neurons, as revealed by TH immunolabeling. The origin of transplanted cells were further confirmed by positive immunolabeling with anti-human nuclei. Our results suggest that enriching the neuroprogenitor population by magnetic sorting prevents tumor formation and is a prerequisite before cell replacement therapy for Parkinson's disease.
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PMID:Enriched NCAM-positive cells form functional dopaminergic neurons in the rat model of Parkinson's disease. 1697 60

The orphan nuclear receptor Nurr1 is required for the development of the ventral mesencephalic dopaminergic neurons. These are the same neurons that are invariantly lost in patients with Parkinson's disease. Nurr1 mRNA expression is not confined to the developing midbrain, and yet Nurr1 appears to be essential for either the maturation of progenitors into fully post-mitotic dopaminergic neurons and/or once formed, their survival. The function of Nurr1 in the transactivation of gene(s) important for neuronal development and/or maintenance is uncharacterized. To characterize potential downstream target genes of Nurr1, we sought to identify mRNAs that are differentially affected by Nurr1 expression. Using a dopaminergic cell line in which Nurr1 content was tightly regulated, differential display analysis identified transcripts altered by Nurr1 expression, including the mRNA encoding vasoactive intestinal peptide (VIP). Herein, we demonstrate that Nurr1 regulates VIP mRNA and protein levels, and transactivates the VIP promoter through Nurr1-responsive cis elements. In addition, dopaminergic cells release and utilize VIP to mediate survival when challenged with paraquat. Nurr1 regulation of VIP is also demonstrated in vivo as loss of Nurr1 function results in diminished VIP mRNA levels within the developing midbrain.
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PMID:VIP is a transcriptional target of Nurr1 in dopaminergic cells. 1699 55

Dopamine belongs to the most intensively studied neurotransmitters of the brain, because of its implications in psychiatric and neurological disorders. Although, clinical relevance of midbrain dopaminergic (mDA) neurons is well recognized and dopaminergic dysfunction may have a genetic component, the genetic cascades underlying developmental processes are still largely unknown. With the advances in molecular biology, mDA neurons and their involvement in psychiatric and neurological disorders are now subject of studies that aim to delineate the fundamental neurobiology of these neurons. These studies are concerned with developmental processes, cell-specific gene expression and regulation, molecular pharmacology, and genetic association of dopamine-related genes and mDA-associated disorders. Several transcription factors implicated in the post-mitotic mDA development, including Nurr1, Lmx1b, Pitx3, and En1/En2 have contributed to the understanding of how mDA neurons are generated in vivo. Furthermore, these studies provide insights into new strategies for future therapies of Parkinson's Disease (PD) using stem cells for engineering DA neurons in vitro. Here, we will discuss the role of Pitx3 in molecular mechanisms involved in the regional specification, neuronal specification and differentiation of mDA neurons.
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PMID:The role of Pitx3 in survival of midbrain dopaminergic neurons. 1701 9

The production of dopamine (DA) neurons from neural progenitor cells (NPC) is of particular interest as these neurons degenerate in Parkinson's disease. Here, we report that the characteristics of NPC from the ventral midbrain (NPC(VM)) and the striatum (NPC(STR)) are intrinsically determined. A detailed analysis of the VM during development revealed Ngn2 and Mash1 expression in a DA progenitor domain. Interestingly, over-expression of either Ngn2 or Mash1 induced neurogenesis from expanded NPC(VM). Whereas Ngn2 inhibited cell division and the production of neurons even in the presence of mitogens, Mash1 allowed the progenitors to divide while retaining neurogenic potential. However, none of the new neurons derived by over-expressing Ngn2 or Mash1 were positive for DA neuronal markers such as tyrosine hydroxylase. Nurr1 over-expression increased TH levels in a dose-dependant manner within both neurons and glia, suggesting a non-neuronal-specific activation of this enzyme by Nurr1. Double infection with Nurr1 and either Ngn2 or Mash1 resulted in the production of small numbers of TH+ neurons, which were larger in size when derived from NPC(VM) compared to NPC(STR). These data provide proof of concept that over-expression of multiple transcription factors can drive the fate of NPC first towards neurons, and then towards the DA phenotype. However, further factors may be required to generate fully functional DA neurons.
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PMID:Control of neurogenesis and tyrosine hydroxylase expression in neural progenitor cells through bHLH proteins and Nurr1. 1703 91

Carnosol, a major component of Rosmarinus officinalis, is a phenolic diterpene that has potent antioxidant and anti-inflammatory activities. In this study, we investigated the protective effects of carnosol on rotenone-induced neurotoxicity in cultured dopaminergic cells. Results showed that cell viability was significantly improved with carnosol through downregulation of caspase-3. Furthermore, carnosol significantly increased the tyrosine hydroxylase, Nurr1, and extracellular signal-regulated kinase 1/2. These results suggest that carnosol may have potential as a possible compound for the development of new agents to treat Parkinson's disease.
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PMID:Carnosol, a component of rosemary (Rosmarinus officinalis L.) protects nigral dopaminergic neuronal cells. 1704 62


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