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)

We examined the cell proliferative, neurogenic, and behavioral effects of transforming growth factor alpha (TGFalpha) in a 6-OHDA Parkinson's disease model when compared with naive rats. Intrastriatal TGFalpha infusion induced significant proliferation, hyperplastic nodules, and substantial migratory waves of nestin-positive progenitor cells from the adult subventricular zone (SVZ) of dopamine-denervated rats. Interestingly, SVZ cells in naive rats displayed proliferation but minimal migration in response to the TGFalpha infusion. The cells in the expanded SVZ accumulated cytoplasmic beta-catenin, indicating activation of classical Wnt signaling. However, no evidence of any neuronal differentiation was found of these recruited progenitor cells anywhere examined in the brain. Consequently, no evidence of dopaminergic (DA) neurogenesis was found in the striatum or substantia nigra in any experimental group, and amphetamine-induced behavioral rotations did not improve. In summary, the cells in the TGFalpha-induced migratory cellular wave remain undifferentiated and do not differentiate into midbrain-like DA neurons.
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PMID:Intrastriatal transforming growth factor alpha delivery to a model of Parkinson's disease induces proliferation and migration of endogenous adult neural progenitor cells without differentiation into dopaminergic neurons. 1548 11

Wnts are important regulators of dopamine (DA) neuron differentiation in the developing ventral mesencephalon and could thus serve as potential tools in the treatment of Parkinson's disease. In this study, we investigate whether established intracellular Wnt signalling components could modulate the development of DA neurons. Two chemical inhibitors of glycogen synthase kinase (GSK)-3beta, indirubin-3-monoxime and kenpaullone, were found to increase neuronal differentiation in ventral mesencephalon precursor cultures. In addition, the GSK-3beta-specific inhibitor kenpaullone increased the size of the DA neuron population through conversion of precursors expressing the orphan nuclear receptor-related factor 1 into tyrosine hydroxylase positive neurons, thereby mimicking an effect of Wnts. We show that GSK-3beta inhibitors stabilized beta-catenin and that overexpression of beta-catenin in ventral mesencephalic precursors resulted in increased DA differentiation. The three- to fivefold increase in DA differentiation of precursor cells by GSK-3beta inhibitors suggests that such compounds could be used to improve stem/precursor cell therapy approaches in Parkinson's disease.
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PMID:GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons. 1552 89

We cloned and characterized human FGF20 in August, 2000. Ohmachi et al claimed the same gene as a novel FGF family member in October, 2000, and Jeffers et al in April, 2001. FGF20 is up-regulated in colorectal cancer due to the activation of WNT/beta-catenin pathway. FGF20 is applicable as the mucosal protective agent for inflammatory bowel disease and chemotherapy/radiation-induced oral mucositis, and also as the inducer of dopaminergic neurons for Parkinson's disease. FGF20 is a target of pharmacogenomics in the field of oncology and regenerative medicine. Here, comparative genomics analyses on FGF20 orthologs were performed. Zebrafish fgf20 gene, consisting of three exons, was located within BX323810.8 genome sequence. Zebrafish fgf20 (208 aa) showed 76.9%, 76.4%, 76.0% and 75.5% total-amino-acid identity with human FGF20, Xenopus fgf20, rat Fgf20 and mouse Fgf20, respectively. Fgf20 orthologs were well conserved among vertebrates. Human FGF20 gene was linked to EFHA2 gene in head-to-head manner with an interval of about 25 kb. FGF20-EFHA2 locus at human chromosome 8p22 and FGF9-EFHA1 locus at human chromosome 13q12.11 were paralogous regions (paralogons) within the human genome. The 5'-flanking promoter region, exonic regions except 3'-UTR, and middle regions within intron 1 were conserved between human FGF20 and mouse Fgf20 genes. Double TCF/LEF binding sites, double EVI1-binding sites, TGIF, PAX4, E47 and AREB6-binding sites were conserved between human FGF20 promoter and mouse Fgf20 promoter.
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PMID:Comparative genomics on FGF20 orthologs. 1594 4

In addition to the well-documented mood-stabilizing effects of lithium in manic-depressive illness patients, recent in vitro and in vivo studies in rodents and humans have increasingly implicated that lithium can be used in the treatment of acute brain injuries (e.g., ischemia) and chronic neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, tauopathies, and Huntington's disease). Consistent with this novel view, substantial evidences suggest that depressive illness is not a mere neurochemical disease, but is linked to gray matter atrophy due to the reduced number/size of neurons and glia in brain. Importantly, neurogenesis, that is, birth/maturation of functional new neurons, continues to occur throughout the lifetime in human adult brains (e.g., hippocampus); the neurogenesis is impaired by multiple not-fully defined factors (e.g., aging, chronic stress-induced increase of glucocorticoids, and excitotoxicity), accounting for brain atrophy in patients with depressive illness and neurodegenerative diseases. Chronic treatment of lithium, in agreement with the delayed-onset of mood-stabilizing effects of lithium, up-regulates cell survival molecules (e.g., Bcl-2, cyclic AMP-responsive element binding protein, brain-derived neurotrophic factor, Grp78, Hsp70, and beta-catenin), while down-regulating pro-apoptotic activities (e.g., excitotoxicity, p53, Bax, caspase, cytochrome c release, beta-amyloid peptide production, and tau hyperphosphorylation), thus preventing or even reversing neuronal cell death and neurogenesis retardation.
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PMID:Lithium: potential therapeutics against acute brain injuries and chronic neurodegenerative diseases. 1634 Jan 57

Dopaminergic (DA) neurons in the ventral midbrain (VM) are one of the major cell types lost in Parkinson's disease (PD). Proof of principle exists for cell replacement therapies for PD, but wider application is halted by the unavailability of abundant sources of DA neurons. Stem cells might constitute one of these sources. However, efficient protocols promoting their specific differentiation into a DA neuronal phenotype are required. In this review, we summarize the latest findings concerning the contribution of the Wnt family of glycolipoproteins in the development of VM DA neurons. Regulators of Wnt signaling are involved in several neurodevelopmental processes. Recent results indicate that Wnts are key regulators of proliferation and differentiation of DA precursors during VM neurogenesis and different Wnts have specific and unique activity profiles. Interestingly, chemical inhibitors of glycogen synthase kinase-3beta stabilize beta-catenin and increase DA differentiation in VM precursor cultures. We hereby propose that Wnts are likely to contribute in the future to improve stem/precursor cell replacement therapy approaches to PD.
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PMID:Function of Wnts in dopaminergic neuron development. 1690 30

The orphan nuclear receptor Nurr1 is essential for the development and maintenance of midbrain dopaminergic neurons, the cells that degenerate during Parkinson's disease, by promoting the transcription of genes involved in dopaminergic neurotransmission. Since Nurr1 lacks a classical ligand-binding pocket, it is not clear which factors regulate its activity and how these factors are affected during disease pathogenesis. Since Wnt signaling via beta-catenin promotes the differentiation of Nurr1(+) dopaminergic precursors in vitro, we tested for functional interactions between these systems. We found that beta-catenin and Nurr1 functionally interact at multiple levels. In the absence of beta-catenin, Nurr1 is associated with Lef-1 in corepressor complexes. Beta-catenin binds Nurr1 and disrupts these corepressor complexes, leading to coactivator recruitment and induction of Wnt- and Nurr1-responsive genes. We then identified KCNIP4/calsenilin-like protein as being responsive to concurrent activation by Nurr1 and beta-catenin. Since KCNIP4 interacts with presenilins, the Alzheimer's disease-associated proteins that promote beta-catenin degradation, we tested the possibility that KCNIP4 induction regulates beta-catenin signaling. KCNIP4 induction limited beta-catenin activity in a presenilin-dependent manner, thereby serving as a negative feedback loop; furthermore, Nurr1 inhibition of beta-catenin activity was absent in PS1(-/-) cells or in the presence of small interfering RNAs specific to KCNIP4. These data describe regulatory convergence between Nurr1 and beta-catenin, providing a mechanism by which Nurr1 could be regulated by Wnt signaling.
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PMID:A regulatory circuit mediating convergence between Nurr1 transcriptional regulation and Wnt signaling. 2450 62

Stem cell-based replacement therapy has emerged as a potential strategy to alleviate specific features of movement disorder in Parkinson's disease. However, the current strategy to produce dopamine (DA) neurons from embryonic stem cells has many limitations, including the difficulty of generating DA neurons with high yields. Further insights into the mechanisms that control the neurogenesis of DA neurons will reduce or mitigate such limitations. It is well established that the ventral midbrain (vMB) contains the neurogenic niche that produces DA neurons. However, it is unclear how the microenvironment within this niche controls DA neurogenesis. Here, we show that beta-catenin controls DA neurogenesis by maintaining the integrity of the neurogenic niche and the progression from progenitors to DA neurons. Using conditional gene targeting approaches, we show that regional deletion of beta-catenin in the vMB by using Shh-Cre disrupts adherent junctions of progenitors and the integrity of radial glia in the vMB, which leads to a severe reduction in DA neurogenesis and perturbs the migration and segregation of DA neurons. By contrast, Th-IRES-Cre removes beta-catenin in a subset of neural progenitor cells without perturbing the cellular and structural integrity of the vMB. Interestingly, loss of beta-catenin in Th-IRES-Cre;beta-Ctn(fl/fl) mutants negatively regulates neurogenesis by interfering with the progression of committed progenitors to DA neurons. Taken together, these results provide new insights into the indispensable functions of beta-catenin at multiple stages during DA neurogenesis. They also suggest that beta-catenin-mediated signaling pathways can be targeted to promote and expand DA neurons in cell-based therapeutic strategies.
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PMID:Multiple roles of beta-catenin in controlling the neurogenic niche for midbrain dopamine neurons. 1943 92

striatum of rodents in experimental models of Parkinson's disease. Interestingly, immunohistochemical studies have shown increased levels of PTN expression in the substantia nigra of patients with Parkinson's disease. Since, in other contexts, PTN has been shown to be critical in repair processes in the injured nervous system, the antecedents suggest that PTN could exhibit protective effects in Parkinson's disease. This hypothesis was confirmed when PTN was shown to support survival of dopaminergic neurons and to promote the differentiation of neural stem cells to dopaminergic neurons. These findings suggest a new therapeutic approach in the treatment of Parkinson's disease based on the molecular mechanism of action of PTN. Pleiotrophin receptor, receptor protein tyrosine phosphatase (RPTP) beta/zeta, is found active in monomeric form in neurons and glia within the central nervous system. Pleiotrophin induces dimerization of RPTPbeta/zeta inactivating its phosphatase activity, thus increasing the phosphorylation levels of its substrates such as beta-catenin, Fyn and beta-adducin. These substrates have been shown to be critical for the proliferation of dopaminergic progenitors and the survival and differentiation of dopaminergic neurons. This review summarizes the strong scientific basis to consider blocking RPTPbeta/zeta as a potentially novel therapeutic strategy in the treatment of Parkinson's disease and discusses various starting points to design antagonists of this receptor.
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PMID:Blocking receptor protein tyrosine phosphatase beta/zeta: a potential therapeutic strategy for Parkinson's disease. 1954 69

Parkinson's disease (PD) is caused by degeneration of the dopaminergic (DA) neurons of the substantia nigra but the molecular mechanisms underlying the degenerative process remain elusive. Several reports suggest that cell cycle deregulation in post-mitotic neurons could lead to neuronal cell death. We now show that Parkin, an E3 ubiquitin ligase linked to familial PD, regulates beta-catenin protein levels in vivo. Stabilization of beta-catenin in differentiated primary ventral midbrain neurons results in increased levels of cyclin E and proliferation, followed by increased levels of cleaved PARP and loss of DA neurons. Wnt3a signaling also causes death of post-mitotic DA neurons in parkin null animals, suggesting that both increased stabilization and decreased degradation of beta-catenin results in DA cell death. These findings demonstrate a novel regulation of Wnt signaling by Parkin and suggest that Parkin protects DA neurons against excessive Wnt signaling and beta-catenin-induced cell death.
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PMID:Parkin protects dopaminergic neurons from excessive Wnt/beta-catenin signaling. 1959 2

Embryonic stem cells (ESCs) represent not only a promising source of cells for cell replacement therapy, but also a tool to study the molecular mechanisms underlying cellular signaling and dopaminergic (DA) neuron development. One of the main regulators of DA neuron development is Wnt signaling. Here we used mouse ESCs (mESCs) lacking Wnt1 or the low-density lipoprotein receptor-related protein 6 (LRP6) to decipher the action of Wnt/beta-catenin signaling on DA neuron development in mESCs. We provide evidence that the absence of LRP6 abrogates responsiveness of mESCs to Wnt ligand stimulation. Using two differentiation protocols, we show that the loss of Wnt1 or LRP6 increases neuroectodermal differentiation and the number of mESC-derived DA neurons. These effects were similar to those observed following treatment of mESCs with the Wnt/beta-catenin pathway inhibitor Dickkopf1 (Dkk1). Combined, our results show that decreases in Wnt/beta-catenin signaling enhance neuronal and DA differentiation of mESCs. These findings suggest that: 1) Wnt1 or LRP6 are not strictly required for the DA differentiation of mESCs in vitro, 2) the levels of morphogens and their activity in ESC cultures need to be optimized to improve DA differentiation, and 3) by enhancing the differentiation and number of ESC-derived DA neurons with Dkk1, the application of ESCs for cell replacement therapy in Parkinson's disease may be improved.
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PMID:Wnt/beta-catenin signaling blockade promotes neuronal induction and dopaminergic differentiation in embryonic stem cells. 1972 18


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