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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neural precursor cells provide an expandable source of neurons and glia for basic and translational applications. However, little progress has been made in directing naive neural precursors toward specific neuronal fates such as midbrain dopamine (DA) neurons. We have recently demonstrated that transgenic expression of the nuclear orphan receptor Nurr1 is sufficient to drive dopaminergic differentiation of forebrain embryonic rat neural precursors in vitro. However, Nurr1-induced DA neurons exhibit immature neuronal morphologies and functional properties and are unable to induce behavioral recovery in rodent models of Parkinson's disease (PD). Here, we report on the identification of key genetic factors that drive morphological and functional differentiation of Nurr1-derived DA neurons. We show that coexpression of Nurr1, Bcl-XL, and Sonic hedgehog (SHH) or Nurr1 and the proneural bHLH factor Mash1 is sufficient to drive naive rat forebrain precursors into neurons exhibiting the biochemical, electrophysiological, and functional properties of DA neuron in vitro. On transplantation into the striatum of Parkinsonian rats, precursor cells engineered with Nurr1/SHH/Bcl-XL or Nurr1/Mash1 survived in vivo and differentiated into mature DA neurons that can reverse the behavioral deficits in the grafted animals.
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PMID:Acquisition of in vitro and in vivo functionality of Nurr1-induced dopamine neurons. 1707 87

Transcription factors are fate determining regulatory factors in dopaminergic neuronal development and differentiation. Among them, Nurr1 is the most extensively studied, but the importance of Pitx3 has recently been appreciated. Over-expression of both factors has been utilized to enhance the dopaminergic differentiation of stem cells for transplantation into models of Parkinson's disease. Previous studies however have seen conflicting results regarding the induction of tyrosine hydroxylase expression and dopaminergic differentiation induced by over-expression of Pitx3. Here we show that over-expression of Pitx3 and Nurr1 induced endogenous tyrosine hydroxylase expression as well as a tyrosine hydroxylase promoter-reporter construct in a human non-neuronal and mouse embryonic stem cell lines. Combined simultaneous expression of Nurr1 and Pitx3 however did not lead to enhancement of tyrosine hydroxylase expression over that of either factor alone in either of the cell lines or with either method. These results suggest that other regulatory elements may also be involved in regulation of tyrosine hydroxylase expression. There was also a lack of a correlation between the expression levels of tyrosine hydroxylase with that of the transcription factor constructs. To yield a robust dopaminergic differentiation a combinatorial or successive treatment with different transcription factors may be more effective.
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PMID:Induction of tyrosine hydroxylase expression by the transcription factor Pitx3. 1718 56

An intensive study is underway to evaluate different potential candidates for cell therapy of neurodegenerative disorders such as Parkinson's disease (PD). Availability and lower immunogenicity compared to other sources for stem cell therapy such as bone marrow have made human umbilical cord blood stem cells a considerable source for cell therapy. The present study aimed to investigate differentiation of recently introduced pluripotent cord blood stem cells, known as unrestricted somatic stem cells (USSCs), into cells with neural features in serum-withdrawal medium. Using reverse transcription polymerase chain reaction and immunocytochemistry assays, we have shown the expression of neuron-specific genes following a 2week treatment of USSCs in serum-withdrawal induction medium. In addition, we have found that USSCs and USSC-derived neuron-like cells express transcripts of genes associated with development and/or survival of dopaminergic mesencephalic neurons including En1, En2, Nurr1, Ptx3, Pax2, Wnt1 and Wnt3a. The expression of dopamine-associated genes suggests that these cells may be potential candidates to be used for cell therapy of PD.
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PMID:In vitro differentiation of cord blood unrestricted somatic stem cells expressing dopamine-associated genes into neuron-like cells. 1719 45

Neural precursor (NP) cells from adult mammalian brains can be isolated, expanded in vitro, and potentially used as cell replacement source material for treatment of intractable brain disorders. Reduced ethical concerns, lack of teratoma formation, and possible ex vivo autologous transplantation are critical advantages to using adult NP donor cells over cells from fetal brain tissue or embryonic stem cells. However, the usage of adult NP cells is limited by the ability to induce specific neurochemical phenotypes in these cells. Here, we demonstrate induction of a dopaminergic phenotype in NP cells isolated from the subventricular zone (SVZ) and white matter of rodent adult brains using overexpression of the nuclear receptor Nurr1 in vitro. Forced expression of Nurr1, a transcriptional factor specific to midbrain dopamine (DA) neuron development, caused in the adult cells an acquisition of the DA neurotransmitter phenotype and sufficient differentiation toward morphologically, phenotypically, and ultrastructurally mature DA neurons. Co-expression of neurogenic factor Mash1 and treatment with neurogenic cytokines brain-derived neurotrophic factor and neurotrophin-3 greatly enhanced Nurr1-induced DA neuron yield. The Nurr1-induced DA neurons demonstrated in vitro presynaptic DA neuronal functionality, releasing DA neurotransmitter in response to depolarization stimuli and specific DA reuptake. Furthermore, Nurr1-engineered adult SVZ NP cells survived, integrated, and differentiated into DA neurons in vivo that can reverse the behavioral deficit in the host striatum of parkinsonian rats. These findings open the possibility for the use of precursor cells from adult brains as a cell source for neuronal replacement treatment of Parkinson disease. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Generation of functional dopamine neurons from neural precursor cells isolated from the subventricular zone and white matter of the adult rat brain using Nurr1 overexpression. 1723 94

The striatum -- the largest integrative component of the basal ganglia -- harbors a population of neurons that express the enzyme tyrosine hydroxylase (TH), a faithful marker of dopaminergic neurons. The dopaminergic nature of these neurons is further supported by the fact that they express the dopamine (DA) transporter (DAT) and the nuclear orphan receptor Nurr1, a transcription factor essential for the expression of the DA phenotype by midbrain neurons. The vast majority of these neurons are morphologically similar to the medium-sized aspiny striatal interneurons and they all express the enzyme GAD(65). The striatal TH-positive neurons increase markedly in number in animal models of Parkinson's disease (PD), where striatal DA concentrations are low, but this increase is abolished by L-dopa treatment. Hence, local DA concentrations appear to regulate the numerical density of this ectopic neuronal population, a phenomenon that is more likely the result of a shift in the phenotype of preexistent striatal interneurons rather than the recruitment of newborn neurons that will develop a DA phenotype. Altogether, these findings suggest that striatal TH-positive neurons act as a local source of DA and, as such, are part of a compensatory mechanism that could be artificially enhanced to alleviate or delay PD symptoms.
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PMID:Dopaminergic neurons intrinsic to the striatum. 1728 88

Parkinson's Disease (PD) is a debilitating motor function disorder due primarily to a loss of midbrain dopaminergic neurons and a subsequent reduction in dopaminergic innervation of the striatum. Several attempts have been made to generate dopaminergic neurons from progenitor cell populations in vitro for potential use in cell replacement therapy for PD. However, expanding cells from fetal brain with retained potential for dopaminergic differentiation has proven to be difficult. In this study, we sought to generate mesencephalic dopaminergic (mesDA) neurons from an expanded population of fetal mouse ventral midbrain (VM) progenitors through the use of retroviral gene delivery. We over-expressed Ngn2 and Nurr1, two genes present in the ventral midbrain and important for normal development of mesDA neurons, in multi-passaged neurosphere-expanded midbrain progenitors. We show that over-expression of Ngn2 in these progenitors results in increased neuronal differentiation but does not promote mesDA formation. We also show that over-expression of Nurr1 alone is sufficient to generate tyrosine hydroxylase (TH) expressing cells with an immature morphology, however the cells do not express any additional markers of mesDA neurons. Over-expression of Nurr1 and Ngn2 in combination generates morphologically mature TH-expressing neurons that also express additional mesencephalic markers.
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PMID:Ngn2 and Nurr1 act in synergy to induce midbrain dopaminergic neurons from expanded neural stem and progenitor cells. 1729 94

Both of environmental and genetic factors confer vulnerability to Parkinson's disease (PD). NR4A2 (Nurr1), a member of the steroid/thyroid hormone nuclear receptor superfamily, is essential for the neurogenesis and differentiation of dopaminergic neurons in the midbrain. Brain derived neurotrophic factor (BDNF) deficiency may play a role in the pathogenesis of PD, as the surviving dopaminergic nigrostriatal neurons have reduced levels of BDNF. This study examines whether BDNF V66M (c.196 G --> A) or NR4A2 IVS6 +18insG polymorphism is associated with the risk of Taiwanese PD and the age of onset using a case-control study. The genotype or allele frequency distribution of both BDNF V66M and NR4A2 IVS6 +18insG polymorphisms was not significantly different between the cases and the controls. Neither BDNF nor NR4A2 polymorphism influences PD onset age. Notably, after stratification by sex, female individuals carrying the NR4A2 2G/2G genotype demonstrated a trend toward significant decrease in risk of developing PD (OR = 0.49, 95% CI = 0.25-0.96, P = 0.039). These results suggest that the NR4A2 IVS6 +18insG polymorphism may play a minor role in PD susceptibility among Taiwanese women.
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PMID:Nuclear receptor NR4A2 IVS6 +18insG and brain derived neurotrophic factor (BDNF) V66M polymorphisms and risk of Taiwanese Parkinson's disease. 1742 85

Midbrain dopamine (DA) neurons play an essential role in modulating motor control. Defects in central DA neurons affect a wide range of neurological disorders including Parkinson's disease (PD). The greatest motivation in the field has been the potential use of DA neurons for cell transplantation therapy in Parkinsonian patients. Recent studies indicated that BMSCs could differentiate into DA neurons in vitro as neural stem cells (NSC) and embryonic stem cells (ESC) could. However, there are no direct evidences about functional DA neurons derived from BMSCs. According to the protocols which had been applicated in inducing neuronal stem cells and embryonic stem cells differentiate into DA neurons in vitro, the present study provides a protocol by using 50 micromol/L brain derived neurotrophy factor (BDNF), 10 micromol/L forskolin (FSK) and 10 micromol/L dopamine (DA) to induce BMSCs differentiate into DA neurons. After 2 weeks of differentiation, the cells expressed the character of neurons in ultrastructure. RT-PCR discovered mRNA of NSE (neuron specific enolase), Nurr1, Ptx3, Lmx1b and Tyrosine hydroxylase (TH) were positive. Immunocytochemistry staining indicated the ratio of TH-positive neural cells was significantly increased after induced 2 weeks (24.80 +/- 3.36) % compared to that of induction of 3 days (3.77 +/- 1.77) %. And the DA release was also different between differentiated and undifferentiated cells detected by high performance liquid chromatography (HPLC). That is to say BDNF and FSK and DA can induce BMSCs differentiate into DA neurons in vitro, and the transdifferentiated cells express mature neurons characters. BMSCs might be a suitable and available source for the in vitro derivation of DA neurons and cell transplantation therapy in some central neural system diseases such as PD.
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PMID:[Human bone marrow mesenchymal stem cells differentiated into dopaminergenic neurons in vitro]. 1746 Aug 97

The hallmark of Parkinson's disease (PD OMIM #168600) is the degeneration of the nigral dopaminergic system affecting approximately 1% of the human population older than 65. In pursuit of genetic factors contributing to PD, linkage and association studies identified several susceptibility genes. The majority of these genes are expressed by the dopamine-producing neurons in the substantia nigra. We, therefore, propose expression by these neurons as a selection criterion, to narrow down, in a rational manner, the number of candidate genes in orphan PD loci, where no mutation has been associated thus far. We determined the corresponding human chromosome locations of 1435 murine cDNA fragments obtained from murine expression analyses of nigral dopaminergic neurons and combined these data with human linkage studies. These fragments represent 19 genes within orphan OMIM PD loci. We used the same approach for independent association studies and determined the genes in neighborhood to the peaks with the highest LOD score value. Our approach did not make any assumptions about disease mechanisms, but it, nevertheless, revealed alpha-synuclein, NR4A2 (Nurr1), and the tau genes, which had previously been associated to PD. Furthermore, our transcriptome analysis identified several classes of candidate genes for PD mutations and may also provide insight into the molecular pathways active in nigral dopaminergic neurons.
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PMID:Merging mouse transcriptome analyses with Parkinson's disease linkage studies. 1752 92

Dopamine (DA) neurons derived from stem cells are a valuable source for cell replacement therapy in Parkinson disease, to study the molecular mechanisms of DA neuron development, and for screening pharmaceutical compounds that target DA disorders. Compared with other stem cells, MSCs derived from the adult human bone marrow (BM) have significant advantages and greater potential for immediate clinical application. We report the identification of in vitro conditions for inducing adult human MSCs into DA cells. Using a cocktail that includes sonic hedgehog and fibroblast growth factors, human BM-derived MSCs were induced in vitro to become DA cells in 12 days. Based on tyrosine hydroxylase (TH) expression, the efficiency of induction was determined to be approximately 67%. The cells develop a neuronal morphology expressing the neuronal markers NeuN and beta III tubulin, but not glial markers, glial fibrillary acidic protein and Olig2. As the cells acquire a postmitotic neuronal fate, they downregulate cell cycle activator proteins cyclin B, cyclin-dependent kinase 2, and proliferating cell nuclear antigen. Molecular characterization revealed the expression of DA-specific genes such as TH, Pitx3, Nurr1, DA transporter, and vesicular monoamine transporter 2. The induced MSCs also synthesize and secrete DA in a depolarization-independent manner. The latter observation is consistent with the low expression of voltage gated Na(+) and Ca(2+) channels in the induced MSCs and suggests that the cells are at an immature stage of development likely representing DA neuronal progenitors. Taken together, the results demonstrate the ability of adult human BM-derived MSCs to form DA cells in vitro.
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PMID:Specification of a dopaminergic phenotype from adult human mesenchymal stem cells. 1765 44


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