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)

Growth factors have been shown to be involved in the regulation of division and differentiation of neuroepithelial cells. In the present study we examined the ability of various factors to influence the development of dopamine precursors. Primary neuronal cultures were prepared from the embryonic day 12 (E12) rat ventral mesencephalon, a time and place which coincides with the beginning of the birth of the dopamine neurons of the substantia nigra pars compacta. At low plating density in serum-free medium, the dopamine precursors divide for approximately 1 d in vitro. We report here that basic fibroblast growth factor (bFGF) can expand the period of dopamine precursor division at least until day 8 in culture, which is well beyond the normal division of these cells. This increase in cell division was accompanied by a delay in differentiation as compared to untreated control cultures. Upon differentiation, the high-affinity dopamine uptake values in bFGF-treated cultures were 20 times maximal control values. Mature dopamine neurons appeared at the same time as astrocytes, which may be playing a role in inducing dopamine neuron differentiation. IGF-I, GDNF, and EGF were unable to mimic the effect of bFGF on division and differentiation of dopamine precursors. Expanding in vitro the number of dopamine precursors provides tissue that may be suitable for transplantation in patients with Parkinson's disease.
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PMID:Basic fibroblast growth factor increases division and delays differentiation of dopamine precursors in vitro. 747 68

Chromaffin cells grafted to the brain of animals with experimental parkinsonism and patients with Parkinson's disease can restore nigrostriatal functions. Mechanisms underlying these beneficial effects are unknown, but may include growth factors rather than the minute amounts of dopamine (DA) liberated from chromaffin cells. We now report that protein from chromaffin granules, which release their contents by exocytosis, promotes survival and uptake of 3H-DA of mesencephalic DAergic neurons in vitro and protect against N-methylpyridinium ion toxicity. This neurotrophic effect is accompanied by cell proliferation and mediated by astroglial cells induced in these cultures. Inhibition of cell proliferation and concomitant astrogliosis by 5-fluorodeoxyuridine and alpha-aminoadipic acid abolishes the trophic effect. Two highly specific inhibitors of the epidermal growth factor receptor (EGFR) signal transduction pathway, 4,5-dianilinophthalimide (10 microM) and tyrphostin B56 (10 microM), selectively block the neurotrophic capacity of chromaffin granule protein. As expected, they also block the mitogenic effects of EGF and TGF-alpha. However, these two mitogens do not mimic the pronounced mitogenic and trophic actions of chromaffin granule protein. Culture medium conditioned by mesencephalic cells pretreated with chromaffin granule protein promotes survival of DAergic neurons without increasing numbers of astroglial cells. The effective molecule is unlikely to be glial cell line-derived neurotrophic factor, whose mRNA is not detectable in cultures treated with chromaffin granule protein. We conclude that chromaffin granules contain a putatively novel growth factor, which signals through the EGFR and may be responsible for the known protective and restorative actions of chromaffin cell grafts to the lesioned nigrostriatal system.
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PMID:Protein from chromaffin granules promotes survival of mesencephalic dopaminergic neurons by an EGF-receptor ligand-mediated mechanism. 908 78

Since EGF is known to protect and stimulate the activity of dopaminergic neurons, an autoradiographic study of [125I]EGF binding sites was performed in the striatum and pallidal complex in parkinsonian syndromes. The analysis was performed on postmortem brain tissues of three control subjects, three patients with Parkinson's disease, and three patients with progressive supranuclear palsy, another parkinsonian syndrome in which dopaminergic neurons also degenerate. Since all six patients had been treated with L-Dopa, we also analyzed the effects of this drug in an animal model of Parkinson's disease. Quantitative analysis of [125I]EGF binding was performed on the brains of three control monkeys, nine monkeys rendered parkinsonian by MPTP intoxication, three of which were treated with L-Dopa. An increased density of [125I]EGF binding was observed at anterior levels in the dorsal striatum, but not in the pallidum, of patients with Parkinson's disease and progressive supranuclear palsy. [125I]EGF binding was unchanged in parkinsonian monkeys whether or not they had been treated with L-Dopa. The data suggest an increased expression of EGFRs in the striatum in chronic parkinsonian syndromes but not in acute models of the disease.
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PMID:[125I]EGF binding in basal ganglia of patients with Parkinson's disease and progressive supranuclear palsy and in MPTP-treated monkeys. 987 76

Neural stem cells (NSCs) are multipotent and widely used in many research fields such as transplantation. Hypoxia not only improves the proliferation of various stem cells in vitro but also plays an important role in the differentiation of stem cells. The aim of the present study was to investigate the effect of hypoxia on the differentiation of NSCs. NSCs were isolated from the midbrain of embryonic Wistar rats (E13.5d), and cultured in serum-free DMEM/F12 medium (containing 20 ng/mL EGF, 20 ng/mL bFGF, 1% N2 and B27). The neurospheres were passaged every 3-5 d, and the third generation of NSCs was used for the following experiments. NSCs were induced under normoxia (20% O2) and hypoxia (3% O2), respectively, for 3 d, and then differentiated under normoxia for 5-7 d (DMEM/F12 medium containing 1% FBS, N2 and B27). Immunohistochemistry of nestin, NeuN and TH was used for NSC identification and differentiation assay. The number of TH-positive cells was evaluated by flow cytometry. Dopamine (DA) content in the supernatant of culture medium was detected by HPLC. The results showed that NSCs could self-renew and were all nestin-positive. NSCs under hypoxic condition differentiated more neurons than those under normoxic condition. The percentage of TH-positive cells differentiated from NSCs under normoxia and hypoxia was (10.25+/-1.03) % and (19.88+/-1.44) %, respectively. In addition, DA content in the supernatant of culture medium in hypoxia group increased significantly, about twice of that in normoxia group (P<0.05, n=8). The results demonstrate that hypoxia (3% O2) promotes the differentiation of NSCs into neurons, especially dopaminergic neurons. It is suggested that hypoxia may be a potential clinical tool to treat Parkinson's disease.
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PMID:[Hypoxia promotes the differentiation of neural stem cells into dopaminergic neurons]. 1757 80

We report the generation of functional dopaminergic neurons from human embryonic stem cells (hESCs) using a growth factor mediated multistep EB protocol and its therapeutic effects in vivo. Embryoid bodies (EBs) were cultured in insulin-transferrin-selenium fibronectin (ITSFn) media for the selection of neural precursor cells (NPC). The selected cells on exposure to N2 media supplemented with EGF, bFGF initially aggregated to generate spontaneous free floating neurospheres and on exposure to signaling molecules Shh and FGF-8 differentiated into dopaminergic neurons (40% TH+ cells/total neurons). The differentiated NPC expressed dopaminergic specific markers both at cellular and molecular levels. They secreted detectable levels of dopamine into the culture supernatant. The most unique feature of our protocol is the generation of free floating neurospheres which can be expanded for a longer period without losing their capability to differentiate into DA neurons. Further, transplantation of NPCs into the substantia nigra of 6-OHDA lesioned rat model of Parkinson's disease elicited significant reversal of lesion induced motor deficits which was sustained upto the end of 1 year long study period. Immunohistochemical studies of the grafted area one year post transplantation revealed that transplanted hESC derived neural precursor cells survived, integrated in vivo and differentiated into dopaminergic neurons without teratoma formation. In summary, our results encourage the potential use of hESC derived dopaminergic neurons for future clinical application in Parkinson's disease.
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PMID:One year survival and significant reversal of motor deficits in parkinsonian rats transplanted with hESC derived dopaminergic neurons. 1856 28

A reduction in dopaminergic innervation of the subventricular zone (SVZ) is responsible for the impaired proliferation of its resident precursor cells in this region in Parkinson's disease (PD). Here, we show that this effect involves EGF, but not FGF2. In particular, we demonstrate that dopamine increases the proliferation of SVZ-derived cells by releasing EGF in a PKC-dependent manner in vitro and that activation of the EGF receptor (EGFR) is required for this effect. We also show that dopamine selectively expands the GFAP(+) multipotent stem cell population in vitro by promoting their self-renewal. Furthermore, in vivo dopamine depletion leads to a decrease in precursor cell proliferation in the SVZ concomitant with a reduction in local EGF production, which is reversed through the administration of the dopamine precursor levodopa (L-DOPA). Finally, we show that EGFR(+) cells are depleted in the SVZ of human PD patients compared with age-matched controls. We have therefore demonstrated a unique role for EGF as a mediator of dopamine-induced precursor cell proliferation in the SVZ, which has potential implications for future therapies in PD.
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PMID:Dopamine-induced proliferation of adult neural precursor cells in the mammalian subventricular zone is mediated through EGF. 1943 89

In this chapter we review work on neurotrophic factors for midbrain dopaminergic neurons mainly from the past decade, with a focus on neurotrophins and fibroblast growth factors. We summarize data obtained from animal models of Parkinson's disease, review analyses of neurotrophin, neurotrophin receptor and FGF-2 knockout mice and put these into context with data obtained from patients with Parkinson's disease and from postmortem studies. We provide a brief overview on several other factors (EGF, TGF-alpha, IGF, CNTF, PDGF, interleukins) and their capacity to promote survival and protect lesioned DAergic neurons. TGF-betas are reviewed in a separate chapter (Roussa et al, this volume).
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PMID:Neurotrophic support of midbrain dopaminergic neurons. 1973 52

Growing evidence has demonstrated that neurogenesis in the subventricular zone (SVZ) is significantly decreased in Parkinson's disease (PD). Modulation of endogenous neurogenesis would have a significant impact on future therapeutic strategies for neurodegenerative diseases. In the present study, we investigated the augmentative effects of human mesenchymal stem cells (hMSCs) on neurogenesis in a PD model. Neurogenesis was assessed in vitro with 1-methyl-4-phenylpyridinium (MPP(+)) treatment using neural precursor cells (NPCs) isolated from the SVZ and in vivo with a BrdU-injected animal model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immunochemical analyses were used to measure neurogenic activity. The number of BrdU-ir cells in the SVZ and the substantia nigra (SN) was significantly increased in the hMSC-treated PD group compared with the MPTP-only-treated group. Double-stained cells for BrdU and tyrosine hydroxylase were notably observed in the SN of hMSC-treated PD animals, and they did not colocalize with the nuclear matrix; however, double-stained cells were not detected in the SN of the MPTP-induced PD animal model. Furthermore, hMSC administration increased the expression of the epidermal growth factor receptor (EGFR) in the SVZ of PD animals, and the coculture of hMSCs significantly increased the release of EGF in the medium of MPP(+)-treated NPCs. The present study demonstrated that hMSC administration significantly augmented neurogenesis in both the SVZ and SN of PD animal models, which led to increased differentiation of NPCs into dopaminergic neurons in the SN. Additionally, hMSC-induced modulation of EGF seems to be an underlying contributor to the enhancement of neurogenesis by hMSCs. The modulation of endogenous adult neurogenesis to repair the damaged PD brain using hMSCs would have a significant impact on future strategies for PD treatment.
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PMID:Mesenchymal stem cells augment neurogenesis in the subventricular zone and enhance differentiation of neural precursor cells into dopaminergic neurons in the substantia nigra of a parkinsonian model. 2254 97

Genetic studies show that LRRK2, and not its closest paralogue LRRK1, is linked to Parkinson's disease. To gain insight into the molecular and cellular basis of this discrepancy, we searched for LRRK1- and LRRK2-specific cellular processes by identifying their distinct interacting proteins. A protein microarray-based interaction screen was performed with recombinant 3xFlag-LRRK1 and 3xFlag-LRRK2 and, in parallel, co-immunoprecipitation followed by mass spectrometry was performed from SH-SY5Y neuroblastoma cell lines stably expressing 3xFlag-LRRK1 or 3xFlag-LRRK2. We identified a set of LRRK1- and LRRK2-specific as well as common interactors. One of our most prominent findings was that both screens pointed to epidermal growth factor receptor (EGF-R) as a LRRK1-specific interactor, while 14-3-3 proteins were LRRK2-specific. This is consistent with phosphosite mapping of LRRK1, revealing phosphosites outside of 14-3-3 consensus binding motifs. To assess the functional relevance of these interactions, SH-SY5Y-LRRK1 and -LRRK2 cell lines were treated with LRRK2 kinase inhibitors that disrupt 14-3-3 binding, or with EGF, an EGF-R agonist. Redistribution of LRRK2, not LRRK1, from diffuse cytoplasmic to filamentous aggregates was observed after inhibitor treatment. Similarly, EGF induced translocation of LRRK1, but not of LRRK2, to endosomes. Our study confirms that LRRK1 and LRRK2 can carry out distinct functions by interacting with different cellular proteins. LRRK1 and LRRK2 (leucine-rich repeat kinase) interaction partners were identified by two different protein-protein interaction screens. These confirmed epidermal growth factor receptor (EGR-R) as a LRRK1-specific interactor, while 14-3-3 proteins were LRRK2-specific. Functional analysis of these interactions and the pathways they mediate shows that LRRK1 and LRRK2 signaling do not intersect, reflective of the differential role of both LRRKs in Parkinson's disease.
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PMID:Differential protein-protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways. 2494 32

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of nigrostriatal dopaminergic (DAergic) neurons and the depletion of striatal dopamine. Here we show that DAergic-neuron-like cells could be efficiently induced from stem cells derived from human exfoliated deciduous teeth (SHEDs), and that these induced cells had therapeutic benefits in a 6-OHDA-induced Parkinsonian rat model. In our protocol, EGF and bFGF signaling activated the SHED's expression of proneural genes, Ngn2 and Mash1, and subsequent treatment with brain-derived neurotrophic factor (BDNF) promoted their maturation into DAergic neuron-like SHEDs (dSHEDs). A hypoxic DAergic differentiation protocol improved cell viability and enhanced the expression of multiple neurotrophic factors, including BDNF, GDNF, NT-3, and HGF. Engrafted dSHEDs survived in the striatum of Parkinsonian rats, improved the DA level more efficiently than engrafted undifferentiated SHEDs, and promoted the recovery from neurological deficits. Our findings further suggested that paracrine effects of dSHEDs contributed to neuroprotection against 6-OHDA-induced neurodegeneration and to nigrostriatal tract restoration. In addition, we found that the conditioned medium derived from dSHEDs protected primary neurons against 6-OHDA toxicity and accelerated neurite outgrowth in vitro. Thus, our data suggest that stem cells derived from dental pulp may have therapeutic benefits for PD.
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PMID:Dopaminergic differentiation of stem cells from human deciduous teeth and their therapeutic benefits for Parkinsonian rats. 2586 32


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