Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DJ-1/PARK7, a cancer- and Parkinson's disease (PD)-associated protein, protects cells from toxic stresses. However, the functional basis of this protection has remained elusive. We found that loss of DJ-1 leads to deficits in NQO1 [NAD(P)H quinone oxidoreductase 1], a detoxification enzyme. This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination. Without intact DJ-1, Nrf2 protein is unstable, and transcriptional responses are thereby decreased both basally and after induction. This effect of DJ-1 on Nrf2 is present in both transformed lines and primary cells across human and mouse species. DJ-1's effect on Nrf2 and subsequent effects on antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD, which are seemingly disparate disorders. Furthermore, this DJ-1/Nrf2 functional axis presents a therapeutic target in cancer treatment and justifies DJ-1 as a tumor biomarker.
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PMID:DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. 1701 34

The Parkinsonian syndrome induced by pesticides is associated with the impairment of mitochondrial function. Toxicants that inhibit selectively NADH-dehydrogenase activity, as rotenone or pyridaben, also show a selective inhibition of O2 uptake and respiratory control in rat brain mitochondria in the presence of NAD-dependent substrates. The IC50 of rotenone and pyridaben for complex I inhibition were in the range 1.7-2.2 microM. The determination of NADH-cytochrome c reductase, succinate-cytochrome c reductase and cytochrome oxidase activities in rat brain submitochondrial showed again the selective inhibition of Complex I by rotenone and pyridaben, whereas paraquat produced a non-selective inhibition affecting all the respiratory chain complexes. In rat brain mitochondria, rotenone and pyridaben markedly decreased mtNOS functional activity with NAD-dependent substrates but not when the substrate was succinate. This observation suggest than mtNOS activity is regulated by the activity of complex I. This regulation and the role of mitochondrial NO diffusion as a signal for mitochondrial biogenesis could have a role in the etiopathology of Parkinson's disease.
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PMID:Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome. 1712 63

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a selective loss of dopaminergic neurons in the substantia nigra. Evidence suggests oxidation of dopamine (DA) to DA quinone and consequent oxidative stress as a major factor contributing to this vulnerability. We have previously observed that exposure to or induction of NAD(P)H:quinone reductase (QR1), the enzyme that catalyzes the reduction of quinone, effectively protects DA cells. Sulforaphane (SF) is a drug identified as a potent inducer of QR1 in various non-neuronal cells. In the present study, we show that SF protects against compounds known to induce DA quinone production (6-hydroxydopamine and tetrahydrobiopterin) in DAergic cell lines CATH.a and SK-N-BE(2)C as well as in mesencephalic DAergic neurons. SF leads to attenuation of the increase in protein-bound quinone in tetrahydrobiopterin-treated cells, but this does not occur in cells that have been depleted of DA, suggesting involvement of DA quinone. SF pretreatment prevents membrane damage, DNA fragmentation, and accumulation of reactive oxygen species. SF causes increases in mRNA levels and enzymatic activity of QR1 in a dose-dependent manner. Taken together, these results indicate that SF causes induction of QR1 gene expression, removal of intracellular DA quinone, and protection against toxicity in DAergic cells. Thus, this major isothiocyanate found in cruciferous vegetables may serve as a potential candidate for development of treatment and/or prevention of PD.
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PMID:Protective effect of sulforaphane against dopaminergic cell death. 1725 50

Ceramide is a lipid second-messenger generated in response to stimuli associated with neurodegeneration that induces apoptosis, a mechanism underlying neuronal death in Parkinson's disease. We tested the hypothesis that insulin-like growth factor-1 (IGF-1) could mediate a metabolic response in CAD cells, a dopaminergic cell line of mesencephalic origin that differentiate into a neuronal-like phenotype upon serum removal, extend processes resembling neurites, synthesize abundant dopamine and noradrenaline and express the catecholaminergic biosynthetic enzymes tyrosine hydroxylase and dopamine beta-hydroxylase, and that this process was phosphatidylinositol 3-kinase (PI 3-K)-Akt-dependent and could be inhibited by C(2)-ceramide. The metabolic response was evaluated as real-time changes in extracellular acidification rate (ECAR) using microphysiometry. The IGF-1-induced ECAR response was associated with increased glycolysis, determined by increased NAD(P)H reduction, elevated hexokinase activity and Akt phosphorylation. C(2)-ceramide inhibited all these changes in a dose-dependent manner, and was specific, as it was not induced by the inactive C(2)-ceramide analogue C(2)-dihydroceramide. Inhibition of the upstream kinase, PI 3-K, also inhibited Akt phosphorylation and the metabolic response to IGF-1, similar to C(2)-ceramide. Decreased mitochondrial membrane potential occurred after loss of Akt phosphorylation. These results show that IGF-1 can rapidly modulate neuronal metabolism through PI 3-K-Akt and that early metabolic inhibition induced by C(2)-ceramide involves blockade of the PI 3-K-Akt pathway, and may compromise the first step of glycolysis. This may represent a new early event in the C(2)-ceramide-induced cell death pathway that could coordinate subsequent changes in mitochondria and commitment of neurons to apoptosis.
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PMID:Insulin-like growth factor-1-dependent maintenance of neuronal metabolism through the phosphatidylinositol 3-kinase-Akt pathway is inhibited by C2-ceramide in CAD cells. 1756 16

A recent study has identified selective inhibitors of the human silent information regulator 2 NAD (+)-dependent protein deacetylase, SIRT2, and has shown that these compounds protect against alpha-synuclein-mediated toxicity in cellular models of Parkinson's disease. The inhibitors were found to ameliorate dopaminergic cell death in vitro and in a Drosophila model of Parkinson's disease. Although the molecular mechanism of action is unclear, the compounds may function by promoting the formation of enlarged inclusion bodies, which are suggested to provide a cell-survival advantage.
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PMID:Linking SIRT2 to Parkinson's disease. 1770 69

Nicotinamide, the principal form of niacin (vitamin B3), has been proposed to be neuroprotective in Parkinson's disease. However, the effects and mechanisms of nicotinamide on motor function in animals and on mitochondrial function in cellular systems have not been well studied. We hypothesized that niacin-derived NAD(P)H as antioxidants and enzyme cofactors could inhibit oxidative damage and improve mitochondrial function and thus protect neurodegeneration and improve motor function. In the present study, the effects of nicotinamide on mitochondrial function and oxidative stress were studied in a 1-methyl-4-phenylpyridinium (MPP(+))-induced cellular model of Parkinson's disease, and the effects of improving motor dysfunction were studied in an alpha-synuclein transgenic Drosophila Parkinson's model. Mitochondrial function was tested by measuring the activity of mitochondrial complex I and alpha-ketoglutarate dehydrogenase, and oxidative damage was tested by measuring reactive oxygen species, DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanosine and Comet assay), and protein oxidation (protein carbonyls) levels. Nicotinamide at a relatively higher concentration, that is, 100-fold of the level in the cell culture medium (101 mg/L), significantly protected SK-N-MC human neuroblastoma cells from an MPP(+)-induced decrease in cell viability, complex I and alpha-ketoglutarate dehydrogenase activity, and an increase in oxidant generation, DNA damage, and protein oxidation. In the Drosophila model, nicotinamide at 15 and 30 mg/100 g diet significantly improved climbing ability. These results suggest that nutritional supplementation of nicotinamide at high doses decreases oxidative stress and improves mitochondrial and motor function in cellular and/or Drosophila models and may be an effective strategy for preventing and ameliorating Parkinson's disease.
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PMID:High doses of nicotinamide prevent oxidative mitochondrial dysfunction in a cellular model and improve motor deficit in a Drosophila model of Parkinson's disease. 1838 61

Homocysteine is an amino acid that is an important risk factor for several neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Increased homocysteine levels induce neuronal cell death in a variety of neuronal types. However, very few studies have probed the effects of homocysteine in astrocytes. The present study investigated the effects of homocysteine on primary cultures of astrocytes by exposing astrocytes to 400 microM homocysteine for 20 h. Metabolic extracts of cells were prepared following a 4-h incubation in minimum medium with 5.5 mM [U-(13)C]glucose in the presence or absence of homocysteine and analysed using (13)C NMR. The expression level of pyruvate dehydrogenase kinase isoform 2 (PDK-2), NAD(P)H levels and mitochondrial membrane potential responses were investigated following culture with homocysteine. Metabolomic analysis was performed using (1)H NMR spectroscopy and pattern recognition analysis. Following incubation with homocysteine there was a significant decrease (48%) in the ratio of flux through pyruvate carboxylase (PC) and pyruvate dehydrogenase (PDH) which was due to an increased flux through PDH. In addition, homocysteine culture resulted in a significant reduction in PDK-2 protein expression. Following stimulation with glucose there was a significant increase in NAD(P)H levels and an impaired hyperpolarisation of the mitochondrial membrane in homocysteine-treated cells. Metabolomic analysis showed that the most discriminating metabolites following homocysteine treatment were choline and hypotaurine. In summary, the results demonstrated that sub-lethal concentrations of homocysteine caused significant metabolic changes and altered mitochondrial function in primary cultures of astrocytes.
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PMID:Effects of homocysteine on metabolic pathways in cultured astrocytes. 1841 55

Parkinson's disease (PD) is a neurodegenerative disorder associated with selective loss of dopaminergic neurons in the substantia nigra. Because oxidative stress caused by dopamine oxidation to dopamine quinone is suggested as a major factor contributing to the pathogenesis of PD, the induction of the enzyme that catalyzes the reduction of quinones, NAD(P)H quinone oxidoreductase1 (NQO1), could be a desirable therapeutic strategy to protect cells from oxidative damage. The dopamine agonist bromocriptine is used clinically for PD therapy. In addition to ameliorating the motor deficit via dopamine D2 receptor activation, bromocriptine also has neuroprotective and antioxidative activity. In the present study, we show that bromocriptine upregulates the expression and activity of NQO1, attenuates the increase in the protein-bound quinone in H(2)O(2)-treated PC12 cells, and protects PC12 cells against oxidative damage. Bromocriptine increases the expression and nuclear translocation of a basic leucine zipper transcription factor, nuclear factor-E2-related factor-2 (Nrf2), which is known to be involved in the regulation of numerous antioxidant enzymes via the antioxidant response element. The Nrf2-related cytoprotective and antioxidative effects of bromocriptine are PI3K/Akt pathway-dependent, and are independent of dopamine receptor activation. The cytoprotective effect of bromocriptine in PC12 cells is not affected by the presence of dopamine D2 antagonist, and the bromocriptine-induced Nrf2-ARE activation and cytoprotection against oxidative stress are observed in both dopamine D2 receptor-expressing A7-D2 and non-expressing A7 cells. Taken together, we investigate the novel cytoprotective effect of bromocriptine involving PI3K- and Nrf2-mediated upregulation of the antioxidant enzyme NQO1.
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PMID:Bromocriptine activates NQO1 via Nrf2-PI3K/Akt signaling: novel cytoprotective mechanism against oxidative damage. 1845 24

Complex I is the main O(2)(-) producer of the mitochondrial respiratory chain. O(2)(-) release is low with NAD-linked substrates and increases strongly during succinate oxidation, which increases the QH(2)/Q ratio and is rotenone sensitive. We show that the succinate dependent O(2)(-) production (measured as H(2)O(2) release) is inhibited by propargylamine containing compounds (clorgyline, CGP 3466B, rasagiline and TVP-1012). The inhibition does not affect membrane potential and is unaffected by DeltapH modifications. Mitochondrial respiration is similarly unaffected. The propargylamines inhibition of O(2)(-)/H(2)O(2) production is monitored also in the presence of the Parkinson's disease toxin dopaminochrome which stimulates O(2)(-) release. Propargylamine-containing compounds are the first pharmacological inhibitors described for O(2)(-) release at Complex I.
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PMID:Clorgyline and other propargylamine derivatives as inhibitors of succinate-dependent H(2)O(2) release at NADH:UBIQUINONE oxidoreductase (Complex I) in brain mitochondria. 1876 29

Epidemiological and experimental studies have correlated hyperhomocysteinemia to a range of neurodegenerative conditions, including Alzheimer's disease, stroke, and Parkinson's disease. Although homocysteine-induced apoptosis in neurons has been extensively studied, little information is available regarding the effect of homocysteine on microglia. In this report, we demonstrated that homocysteine promoted proliferation and up-regulated the expression of CD11b (a marker of microglial activation). Consistent with our in vitro results, a significant increase in the number of CD11b-positive microglia was also observed in brain sections of mice with hyperhomocysteinemia. Homocysteine promoted the activity of NAD(P)H oxidases, resulting in the generation of reactive oxygen species. Up-regulation of NAD(P)H oxidase activity by homocysteine appears to be due to its ability to induce the phosphorylation of p47phox through the p38 MAPK pathway. Furthermore, inhibition of reactive oxygen species significantly blocked cellular proliferation and activation in microglia. Since microglial proliferation and activation play an important role in the development of several neurodegenerative disorders, our results reveal a novel role of homocysteine in the pathogenesis of neurodegenerative diseases.
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PMID:Homocysteine promotes proliferation and activation of microglia. 1913 Nov 43


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