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)

alpha-Synuclein plays a key role in the pathological neurodegeneration in Parkinson's disease. Although its contribution to normal physiology remains elusive, the selective degeneration of alpha-synuclein-containing dopaminergic neurons in Parkinson's disease may be linked to abnormal alpha-synuclein induced toxicity. In the present study, a complex of alpha-synuclein and vesicular monoamine transporter-2 was identified by GST-Pull Down experiment. In wild-type alpha-synuclein stably transfected SH-SY5Y cell lines, the activity of vesicular monoamine transporter-2 decreased by 31% as determined by [(3)H] dopamine uptake, and its expression also decreased in both protein and mRNA levels using western and northern blot analysis. Overexpression of wild-type alpha-synuclein did not induce cell death or apoptosis, but significantly enhanced the intracellular reactive oxygen species level as assayed by flow cytometry. These data suggest that Up-regulated alpha-synuclein expression inhibits the activity of vesicular monoamine transporter-2, thereby interrupting dopamine homeostasis and resulting in dopaminergic neuron injury in Parkinson's disease.
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PMID:Inhibition of vesicular monoamine transporter-2 activity in alpha-synuclein stably transfected SH-SY5Y cells. 1798 33

Attempts were made in the present case-control study to investigate the association of polymorphism in the genes encoding proteins involved in toxication-detoxication and dopaminergic pathways and susceptibility to Parkinson's disease (PD). Seventy patients suffering from PD and one hundred healthy controls belonging to the same geographical location and same ethnicity were included in the study. PCR-RFLP and allele-specific PCR-based methodology were used to identify the genotypes. Multivariate logistic regression analysis revealed that heterozygous genotypes of cytochrome P4502D6*4(CYP2D6*4), CYP2E1*5B (RsaI) polymorphism and homozygous mutant genotypes of CYP2E1*6 (Dra1) were found to be overrepresented in PD cases when compared to the controls. Risk was also found to be increased in patients carrying glutathione S-transferase T1 (GSTT1) null or homozygous variant genotypes of GSTP1. Significant association was observed for monoamine oxidase-B(MAO-B) variant allele G and PD, whereas no difference in genotype and allele frequencies was observed for manganese-superoxide dismutase (MnSOD), dopamine receptor-D2(DRD2), and dopamine transporter (DAT) genes between controls and PD cases. Genotype combinations characterized by the presence of two variant genotypes on their corresponding loci revealed that four combinations of GSTT1 null and MnSOD(-9Val) or GST null and MAOB-G or CYP2E1*5B and MAO-B-AG or CYP2E1*5B and DRD2 (Taq1A-het) genotypes in the patients exhibited severalfold higher and significant association with risk to PD. Our data suggest that polymorphism in the genes involved in detoxification and dopamine regulation may modulate the susceptibility to PD and could be important risk factors in the pathogenesis of PD.
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PMID:Polymorphism in environment responsive genes and association with Parkinson disease. 1832 68

Epidemiological evidence revealed that cigarette smokers and coffee drinkers have lower risk of Parkinson's disease (PD). Nicotine inhibits monoamine oxidase activity, and induces expression of neurotrophic factors and nicotinic acetylcholinergic receptors. However, caffeine is capable of antagonizing adenosine A(2A) receptor. Toxicant responsive enzymes and vesicular monoamine transporter-2 (VMAT-2) play critical roles in chemically induced PD. Despite some known functions, the effects of nicotine and caffeine on the expression and activity of toxicant responsive genes and on VMAT-2 are still not known. The study was therefore undertaken to investigate the effect of nicotine and caffeine on the expression and activity of toxicant responsive genes, i.e., CYP1A1, CYP2E1, GST-ya, GST-yc, GSTA4-4 and VMAT-2 in the striatum of control and MPTP-induced PD phenotype in mouse. The animals were treated intraperitoneally daily with nicotine (1 mg/kg) or caffeine (20 mg/kg) for 8 weeks, followed by 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 20 mg/kg)+nicotine or caffeine for 4 weeks. MPTP significantly attenuated CYP1A1 and VMAT-2, and augmented CYP2E1, GST-ya, GST-yc and GSTA4-4 expression/activity. Nicotine or caffeine-treated animals showed significant restoration against most of the MPTP-induced alterations. The results obtained thus suggest that nicotine and caffeine modulate MPTP-induced alterations in CYP1A1, CYP2E1, GST-ya, GST-yc, GSTA4-4 and VMAT-2 expression/activity.
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PMID:Nicotine and caffeine-mediated modulation in the expression of toxicant responsive genes and vesicular monoamine transporter-2 in 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease phenotype in mouse. 1837 8

The leucine-rich repeat kinase 2 (LRRK2) has been identified as the defective gene at the PARK8 locus causing the autosomal dominant form of Parkinson's disease (PD). Although several LRRK2 mutations were found in familial as well as sporadic PD patients, its physiological functions are not clearly defined. In this study, using yeast two-hybrid screening, we report the identification of Rab5b as an LRRK2-interacting protein. Indeed, our GST pull down and co-immunoprecipitation assays showed that it specifically interacts with LRRK2. In addition, subcellular fractionation and immunocytochemical analyses confirmed that a fraction of both proteins co-localize in synaptic vesicles. Interestingly, we found that alteration of LRRK2 expression by either overexpression or knockdown of endogenous LRRK2 in primary neuronal cells significantly impairs synaptic vesicle endocytosis. Furthermore, this endocytosis defect was rescued by co-expression of functional Rab5b protein, but not by its inactive form. Taken together, we propose that LRRK2, in conjunction with its interaction with Rab5b, plays an important role in synaptic function by modulating the endocytosis of synaptic vesicles.
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PMID:LRRK2 regulates synaptic vesicle endocytosis. 1844 95

The neuroprotective effects of catalpol, an iridoid glycoside isolated from the fresh rehmannia roots, on the behavior and brain energy metabolism in senescent mice induced by d-galactose were assessed. Except control group, mice were subcutaneously injected with d-galactose (150 mg/kg body weight) for 6 weeks. From the fifth week, drug group mice were treated with catalpol (2.5, 5, 10 mg/kg body weight) and piracetam (300 mg/kg body weight) for the last 2 weeks. Behavioral changes including open field test and passive avoidance were examined after drug administration. To determine the brain damage, pathological alterations were measured by hematoxylin and eosin (HE) staining. The activities of lactate dehydrogenase (LDH), glutathione S-transferase (GSH-ST), glutamine synthetase (GS), creatine kinase (CK) in brain cortex and hippocampus were determined using different biochemical methods. Consistent with the cognition deficits, the activities of GSH-ST, GS and CK decreased while the activity of LDH increased in aging mice brain. Administration of catalpol for 2-weeks not only ameliorated cognition deficit, but also reversed the biochemical markers mentioned above and reduced the histological lesions in mouse brain. These results suggest that catalpol has protective effects on memory damage and energy metabolism failure in aging model mice and is worth testing for further preclinical study aimed for senescence or neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD).
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PMID:d-galactose administration induces memory loss and energy metabolism disturbance in mice: protective effects of catalpol. 1857 5

We have examined the occurrence of GSTM1 null, one of the glutathione S-transferase mu genes, in a control and a Parkinson's disease group. By using the polymerase chain reaction (PCR) we found 67% of non-expressors compared with 51% in a control group (chi(1)(2) = 5.535; p < 0.025). These results suggest that a deletion of the GSTM1 gene may be associated with a susceptibility to Parkinson's disease.
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PMID:Determination of the GSTM1 gene deletion frequency in Parkinson's disease by allele specific PCR. 1859 Oct 34

Oxidative stress plays a crucial role in the manifestations of maneb (MB) and paraquat (PQ)-induced toxicity including MB+PQ-induced Parkinson's disease (PD). Polymorphonuclear leukocytes (PMNs) actively participate in the oxidative stress-mediated inflammation and organ toxicity. The present study was undertaken to investigate the MB- and/or PQ-induced alterations in the indices of oxidative stress in rat PMNs. Animals were treated with or without MB and/or PQ in an exposure time dependent manner. In some sets of experiments, the animals were pre-treated with NOS inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG) along with respective controls. A significant increase in myeloperoxidase (MPO), superoxide dismutase (SOD), nitric oxide, iNOS expression and lipid peroxidation (LPO) was observed in PMNs of MB- and/or PQ-treated animals, while catalase and glutathione S-transferase (GST) activities were attenuated. L-NAME and AG significantly reduced the augmented nitrite content, iNOS expression and MPO activity to control level in MB and PQ exposed animals. Although the augmented LPO was also reduced significantly in L-NAME and AG treated rat PMNs, the level was still higher as compared with controls. Alterations induced in SOD and GST activities were not affected by NOS inhibitors. The results thus suggest that MB and/or PQ induce iNOS-mediated nitric oxide production, which in turn increases MPO activity and lipid peroxidation, thereby oxidative stress.
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PMID:The involvement of nitric oxide in maneb- and paraquat-induced oxidative stress in rat polymorphonuclear leukocytes. 1898 85

Oxidative stress and inflammation appear to play a critical role in the progression of Parkinson's disease. As a result, there has been growing interest in antioxidant pathways and how these pathways might be exploited to slow the progressive loss of dopamine neurons. One such pathway that has garnered attention recently is mediated by the transcription factor Nrf2 and is integral in orchestrating cells' antiinflammatory defense. Nrf2 controls the inducible expression of numerous antioxidant and phase 2 detoxification genes, such as glutathione S-transferase, heme oxygenase-1, and NAD(P)H:quinone oxidoreductase 1 (NQO1). Once activated, these genes work synergistically to maintain intracellular redox homeostasis. In this study, we test the hypothesis that Nrf2 activation can protect dopaminergic neurons against 6-hydroxydopamine (6-OHDA)-induced toxicity. Treatment of organotypic nigrostriatal cocultures with either tert-butylhydroquinone (tBHQ) or sulforaphane, known activators of Nrf2, mitigated dopaminergic cell loss. The observed protection appeared to be mediated, at least in part, by an increase in antioxidant activity. Simultaneous treatment of cultures with tBHQ and 6-OHDA increased NQO1 expression 17-fold compared with controls. Overall, these results suggest that Nrf2 may play an important role in cellular protection in neurodegenerative diseases and may be a viable therapeutic target in the future.
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PMID:Nrf2 activators provide neuroprotection against 6-hydroxydopamine toxicity in rat organotypic nigrostriatal cocultures. 1912 16

Expression quantitative trait loci (eQTL) mapping can be used to identify the genetic variations that underlie inherited differences in gene transcription. We performed eQTL mapping by combining whole genome transcriptional data from the hypothalami of 33 strains of inbred mice with a detailed haplotype map of those same strains, revealing 10,655 trans associations and 31 cis eQTLs. One of the cis associations was found to be driven by strain-specific variation in the expression of Glutathione S-transferase, mu 5 (Gstm5). Gstm5 is one of seven members of the glutathione S-transferase, Mu family of genes. The glutathione S-transferases are phase II metabolic enzymes and are key regulators of drug and toxin clearance. In mouse, all seven family members are tightly clustered on mouse chromosome 3. Investigation of the Gstm5 cis association in multiple tissues types revealed that an 84-kilobase region on MMU3 acts as a haplotype-specific locus control region for the glutathione S-transferase, Mu cluster. In the strains that share the minor haplotype, drastic reductions in mRNA levels in multiple members of the Gst Mu family were observed. The strain-specific differences in Gst Mu transcription characterized here accurately model the human population, in which extreme variations in expression of GST Mu family members have been observed. Furthermore, the reduction in Gst Mu levels has important relevance for pharmacology and toxicology studies conducted in these strains. For instance, the reduced levels of Gst Mu in general and Gstm5 in particular have implications in models of dopamine metabolism, Parkinson's disease, and chemical neurotoxicity.
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PMID:Expression quantitative trait loci mapping identifies new genetic models of glutathione S-transferase variation. 1932 42

Neuroprotective effects of alpha(2)-adrenergic receptor (AR) agonists are mediated via the alpha(2A)AR subtype, but the molecular mechanisms underlying these actions are still not elucidated. A two-hybrid screen was performed to identify new proteins that may control alpha(2)AR receptor function and trafficking. This screen identified the ubiquitin carboxyl-terminal hydrolase-L1 (Uch-L1), a protein associated with Parkinson's disease, as alpha(2)AR interacting protein. This interaction was confirmed and evaluated by GST pull down assays demonstrating that Uch-L1 binds preferentially to the alpha(2A)AR subtype and only with less affinity to alpha(2B)AR and alpha(2C)AR. Co-immunoprecipitation of epitope-tagged proteins confirmed the specificity of this interaction in vivo. Moreover, co-transfection of a truncated G-protein coupled receptor kinase-DNA preventing alpha(2)AR phosphorylation led to an increased signal-strength of coimmunoprecipitated Uch-L1. Confocal laser microscopy showed that interaction of alpha(2A)AR and Uch-L1 occurred in the cytoplasm. alpha(2)AR agonist mediated activation of p44/42 MAP Kinase was drastically decreased in the presence of Uch-L1 indicating a functional relevance of this interaction. These findings may present a mechanism contributing to subtype-specific alpha(2)AR trafficking and a potential pathway for the neuroprotective effects of alpha(2)AR agonists.
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PMID:Interaction of the ubiquitin carboxyl terminal esterase L1 with alpha(2)-adrenergic receptors inhibits agonist-mediated p44/42 MAP kinase activation. 1947 70


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