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)

Oxidative stress induced by acute complex I inhibition with 1-methyl-4-phenylpyridinium ion activated biphasically the stress-activated c-Jun N-terminal kinase (JNK) and the early transcription factor nuclear factor-kappaB (NF-kappaB) in SH-SY5Y neuroblastoma cells. Early JNK activation was dependent on mitochondrial adenine nucleotide translocator (ANT) activity, whereas late-phase JNK activation and the cleavage of signaling proteins Raf-1 and mitogen-activated protein kinase (MAPK) kinase (MEK) kinase (MEKK)-1 appeared to be ANT-independent. Early NF-kappaB activation depended on MEK, later activation required an intact electron transport chain (ETC), and Parkinson's disease (PD) cybrid (mitochondrial transgenic cytoplasmic hybrid) cells had increased basal NF-kappaB activation. Mitochondria appear capable of signaling ETC impairment through MAPK modules and inducing protective NF-kappaB responses, which are increased by PD mitochondrial genes amplified in cybrid cells. Irreversible commitment to apoptosis in this cell model may derive from loss of Raf-1 and cleavage/activation of MEKK-1, processes reported in other models to be caspase-mediated. Therapeutic strategies that reduce mitochondrial activation of proapoptotic MAPK modules, i.e., JNK, and enhance survival pathways, i.e., NF-kappaB, may offer neuroprotection in this debilitating disease.
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PMID:Interaction among mitochondria, mitogen-activated protein kinases, and nuclear factor-kappaB in cellular models of Parkinson's disease. 1073 93

Embryonic mouse striatal neurons and human neurons derived from the NT2/hNT stem cell line can be induced, in culture, to express the dopaminergic (DA) biosynthetic enzyme tyrosine hydroxylase (TH). The novel expression of TH in these cells is signaled by the synergistic interaction of factors present in the media, such as fibroblast growth factor 1 (FGF1) and one of several possible coactivators [DA, phorbol 12-myristate 13-acetate (TPA), isobutylmethylxanthine (IBMX), or forskolin]. Similarly, in vivo, it has recently been reported that the expression of TH in the developing midbrain is mediated by the synergy of FGF8 and the patterning molecule sonic hedgehog (Shh). In the present study, we examined whether the putative in vivo DA differentiation factors can similarly signal TH in our in vitro cell systems. We found that FGF8 and Shh induced TH expression in fewer than 2% of NT2/hNT cells and less than 5% of striatal neurons. The latter could be amplified to as much as 30% by increasing the concentration of growth factor 10-fold or by the addition of other competent coactivators (IBMX/forskolin, TPA, and DA). Additivity/inhibitor experiments indicated that FGF8 worked through traditional tyrosine kinase-initiated MAP/MEK signaling pathways. However, the Shh signal transduction cascade remained unclear. These data suggest that cues effective in vivo may be less successful in promoting the differentiation of a DA phenotype in mouse and human neurons in culture. Thus, our ability to generate DA neurons from different cell lines, for use in the treatment of Parkinson's disease, will depend on the identification of appropriate differentiation signals for each cell type under investigation.
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PMID:Sonic hedgehog and FGF8: inadequate signals for the differentiation of a dopamine phenotype in mouse and human neurons in culture. 1131 56

Insoluble alpha-synuclein accumulates in Parkinson's disease, diffuse Lewy body disease, and multiple system atrophy. However, the relationship between its accumulation and pathogenesis is still unclear. Recently, we reported that overexpression of alpha-synuclein affects Elk-1 phosphorylation in cultured cells, which is mainly performed by mitogen-activated protein kinases (MAPKs). We further examined the relationship between MAPK signaling and the effects of alpha-synuclein expression on ecdysone-inducible neuro2a cell lines and found that cells expressing alpha-synuclein had less phosphorylated MAPKs. Moreover, they showed significant cell death when the concentration of serum in the culture medium was reduced. Under normal serum conditions, the addition of the MAPK inhibitor U0126 also caused cell death in alpha-synuclein-expressing cells. Transfection of constitutively active MEK-1 resulted in MAPK phosphorylation in alpha-synuclein-expressing cells and improved cell viability even under reduced serum conditions. Thus, we conclude that alpha-synuclein regulates the MAPK pathway by reducing the amount of available active MAPK. Our findings suggest a mechanism for pathogenesis and thus offer therapeutic insight into synucleinopathies.
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PMID:alpha-Synuclein affects the MAPK pathway and accelerates cell death. 1156 Sep 21

The parkinsonian neurotoxin methylpyridinium (MPP(+)) mimics the neuropathology of Parkinson's disease (PD) and likely kills neurons by inhibiting complex I of the electron transport chain and increasing oxidative stress. We examined the time course of activation/inactivation of multiple pro- and anti-apoptotic signaling pathways in MPP(+)-induced apoptotic death of SH-SY5Y neuroblastoma cells. We found an early increase and later decrease of transcriptional activity of the generally anti-apoptotic nuclear factor kappa-beta (NF-kappa B) and early increases in activating phosphorylation of the anti-apoptotic upstream kinase protein kinase B (PKB, also known as AKT). Sequestration-inducing phosphorylation of pro-apoptotic BAD protein increased early then declined. A small biphasic increase in the generally pro-apoptotic p38 kinase activity paralleled the biphasic rise in NF-kappa B-mediated transcription. Inhibition of p38 kinase with 5 micro M SB203540, inhibition of MEK-ERK with 50 micro M U0126, or inhibition of phosphatidylinositol-3-kinase (PI3K) with 10 micro M LY294002 reduced cell viability by 4, 18 or 37%, respectively, after 24 h. All three kinase inhibitors increased cell death in response to 24 h of MPP(+), with the greatest effect shown by LY294002. Nerve growth factor (NGF) caused an early increase in activating phosphorylation of PKB/AKT and MEK-ERK and increased cell survival during MPP(+) exposure. We found that acute MPP(+) exposure activates multiple interacting death- and survival-promoting pathways. Survival-promoting MEK-ERK and PI3K pathways contribute to viability during MPP(+) exposure, both are activated by NGF, and loss of PI3K-mediated signaling and NF-kappa B-mediated transcription may commit cells irreversibly to apoptosis in this model. It remains unknown to what extent these signaling pathways modulate dopamine neuronal death in PD.
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PMID:Methylpyridinium (MPP(+))- and nerve growth factor-induced changes in pro- and anti-apoptotic signaling pathways in SH-SY5Y neuroblastoma cells. 1236 9

SH-SY5Y neuroblastoma cells exposed to the complex I inhibitor/parkinsonian neurotoxin methylpyridinium ion (MPP(+)) activate both survival and death-promoting signaling pathways and undergo MEK/ERK-dependent, phosphatidylinositol-3 kinase-dependent, and c-Jun kinase-dependent cell death. Because genomic responses to MPP(+) are not extensively characterized, we used nylon cDNA arrays to measure gene expression following exposure to an apoptosis-producing [MPP(+)]. Many changes occurred within 5 min, and all gene expression changes appeared before biochemical and morphological markers of apoptosis. The majority of gene expression changes in SY5Y were not found in rho(0) cells, indicating dependence of these changes on intact electron transport activity. rho(0) cells exposed to MPP(+) produced different expression profiles, indicating the potential for responses independent of complex I inhibition. MPP(+)-induced gene expression patterns in normal SY5Y cells were sensitive to inhibitors of MEK/ERK (UO 126) or phosphatidylinositol-3 kinase (LY 294002), demonstrating regulation of gene expression by these survival-promoting signaling pathways. The primary signaling molecules mediating these MPP(+)-induced gene expression changes are unknown but ultimately utilize MEK/ERK and phosphatidylinositol-3 kinase signaling. Genes suppressed by UO 126 or LY 294002 during MPP(+) exposure may mediate cell survival; those expressed in the presence of UO 126 or LY 294002 may mediate cell death in this in vitro model of Parkinson's disease.
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PMID:Dependence on electron transport chain function and intracellular signaling of genomic responses in SH-SY5Y cells to the mitochondrial neurotoxin MPP(+). 1271 Sep 31

Parkinson's disease is a neurodegenerative disorder associated with the selective death of dopaminergic neurons. Glial cell line-derived neurotrophic factor (GDNF) can protect dopaminergic neurons in several parkinsonian models. We used the dopaminergic cell line MN9D to explore the mechanisms underlying GDNF-mediated protection against the neurotoxin 6-hydroxydopamine (6-OHDA). MN9D cell viability was decreased 24 hr after a 15-min exposure to 6-OHDA (50-1000 microM) as revealed by staining with Hoechst reagent and Trypan blue. The addition of GDNF (10 ng/ml) before, during, and after exposure to 6-OHDA significantly increased the number of viable cells as assessed by Hoechst staining. In contrast, 6-OHDA-induced cell membrane damage was unaffected as measured by Trypan blue exclusion. The PI3K specific inhibitor LY294002 (10-50 microM) blocked GDNF-mediated protection against nuclear condensation, as did the MAPK kinase (MEK) inhibitor U0126 (5- 20 microM). These studies suggest that GDNF can protect dopaminergic cells against some but not all aspects of 6-OHDA-induced toxicity by acting through both PI3K and MAPK signaling pathways.
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PMID:Effects of GDNF on 6-OHDA-induced death in a dopaminergic cell line: modulation by inhibitors of PI3 kinase and MEK. 1281 14

Free cytoplasmic dopamine may be involved in the genesis of neuronal degeneration in Parkinson's disease and other such diseases. We used SH-SY5Y human neuroblastoma cells to study the effect of dopamine on cell death, activation of stress-induced pathways, and expression of alpha-synuclein, the characteristic protein accumulated in Lewy bodies. We show that 100 and 500 microM dopamine causes a 40% and 60% decrease of viability, respectively, and triggers autophagy after 24 hr of exposure, characterized by the presence of numerous cytoplasmic vacuoles with inclusions. Dopamine causes mitochondrial aggregation in adherent cells prior to the loss of functionality. Plasma membrane and nucleus also maintain their integrity. Cell viability is protected by the dopamine transporter blocker nomifensine and the antioxidants N-acetylcysteine and ascorbic acid. Dopamine activates the stress-response kinases, SAPK/JNK and p38, but not ERK/MAPK or MEK, and increases alpha-synuclein expression. Both cell viability and the increase in alpha-synuclein expression are prevented by antioxidants; by the specific inhibitors of p38 and SAPK/JNK, SB203580 and SP600125, respectively; and by the inhibitor of autophagy 3-methyladenine. This indicates that oxidative stress, stress-activated kinases, and factors involved in autophagy up-regulate alpha-synuclein content. The results show that nonapoptotic death pathways are triggered by dopamine, leading to autophagy. These findings should be taken into account in the search for strategies to protect dopaminergic neurons from degeneration.
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PMID:Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells. 1286 68

Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Studies show that anti-apoptotic and neurotrophic agents are suitable candidates to prevent delayed cell death and/or restore neural function. Here we present the nontoxic immunomodulating compound AS101, which has the ability to induce neurite outgrowth and neural differentiation in PC12 cells. The present study shows that components of the ras signaling pathway are crucial for AS101-induced PC12 differentiation. These include p21ras and its downstream effectors, c-raf-1 and MEK, as well as PI3K. Moreover, these components mediate AS101-induced upregulation of p21waf, which is obligatory for AS101-induced PC12 differentiation. Furthermore, nitric oxide plays a significant role in these AS101 activities. Finally, we show that AS101 prevents apoptosis of NGF-differentiated PC12 cells after NGF withdrawal. Taken together, these results suggest that AS101 induces PC12 cell differentiation and survival by activating the ras-ERK1/2 and ras-PI3K signal transduction pathways, as well as inducing NO production. Our findings may be important in understanding the regulation of survival/apoptosis of neurons deprived of neurotropic support. Futhermore the data propose that AS101 may have clinical potential in the treatment of neurodegenerative disorders like Parkinson's disease.
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PMID:Tellurium compound AS101 induces PC12 differentiation and rescues the neurons from apoptotic death. 1503 7

To date, glutathione (GSH) depletion is the earliest biochemical alteration shown in brains of Parkinson's disease patients, but the role of GSH in dopamine cell survival is debated. In this study we show that GSH depletion, produced with GSH synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO), induces selectively neuronal cell death in neuron/glia, but not in neuronal-enriched midbrain cultures and that cell death occurs with characteristics of necrosis and apoptosis. BSO produces a dose- and time-dependent generation of reactive oxygen species (ROS) in neurons. BSO activates extracellular signal-regulated kinases (ERK-1/2), 4 and 6 h after treatment. MEK-1/2 and lipoxygenase (LOX) inhibitors, as well as ascorbic acid, prevent ERK-1/2 activation and neuronal loss, but the inhibition of nitric oxide sintase (NOS), cyclo-oxygenase (COX), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) does not have protective effects. Co-localization studies show that p-ERK-1/2 expression after BSO treatment increased in astrocytes and microglial cells, but not in neurons. Selective metabolic impairment of glial cells with fluoroacetate decreased ERK activation. However, blockade of microglial activation with minocycline did not. Our results indicate that neuronal death induced by GSH depletion is due to ROS-dependent activation of the ERK-1/2 signalling pathway in glial cells. These data may be of relevance in Parkinson's disease, where GSH depletion and glial dysfunction have been documented.
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PMID:Role of extracellular signal-regulated protein kinase in neuronal cell death induced by glutathione depletion in neuron/glia mesencephalic cultures. 1548 97

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been recently identified in families with autosomal dominant late-onset Parkinson disease (PD). The LRRK2 protein consists of multiple domains and belongs to the Roco family, a novel group of the Ras/GTPase superfamily. Besides the GTPase (Roc) domain, it contains a predicted kinase domain, with homology to MAP kinase kinase kinases. Using cell fractionation and immunofluorescence microscopy, we show that LRRK2 is localized in the cytoplasm and is associated with cellular membrane structures. The purified LRRK2 protein demonstrates autokinase activity. The disease-associated I2020T mutant shows a significant increase in autophosphorylation of approximately 40% in comparison to wild-type protein in vitro. This suggests that the pathology of PD caused by the I2020T mutation is associated with an increase rather than a loss in LRRK2 kinase activity.
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PMID:The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. 1632 86


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