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)

The ability of cells to control the balance between the generation and quenching of reactive oxygen species is important in combating potentially damaging effects of oxidative stress. One mechanism that cells use to maintain redox homeostasis is the antioxidant response pathway. Antioxidant response elements (AREs) are cis-acting elements located in regulatory regions of antioxidant and phase II detoxification genes. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a member of the Cap 'n' Collar family of transcription factors that binds to the ARE and regulates the transcription of specific ARE-containing genes such as NAD(P)H:quinone oxidoreductase 1, glutamylcysteine synthetase and heme oxygenase. Activation of Nrf2 results in release from its negative repressor, Kelch-like ECH-associated protein 1 (Keap1), and allows Nrf2 to translocate into the nucleus to induce gene expression. In this study, we demonstrate that increasing Nrf2 activity by various methods, including chemical induction, Nrf2 overexpression or Keap1 siRNA knockdown, protects cells against specific types of oxidative damage. Cells were protected against 6-hydroxydopamine- and 3-morpholinosydnonimine-mediated toxicity but not against 1-methyl-1-4-phenylpyridinium toxicity. As oxidative stress is a hallmark of several neurodegenerative disorders, including Parkinson's disease, pharmacological agents that selectively target the Keap1-Nrf2 pathway may provide a novel neuroprotective strategy for the treatment of these diseases.
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PMID:Increased nuclear factor-erythroid 2 p45-related factor 2 activity protects SH-SY5Y cells against oxidative damage. 1609 30

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 present study investigated expression of alpha-synuclein (alpha-syn), a presynaptic protein involved in the pathogenesis of Parkinson's disease, in erythroid cells. Using various immunological procedures, immunoreactivity of alpha-syn was unambiguously demonstrated in erythroid lineage in murine bone marrows and peripheral erythrocytes. Expression of alpha-syn mRNA was also confirmed by in situ hybridization. Furthermore, flow cytometry analysis revealed that approximately 80% of erythroid cells in murine bone marrows expressed alpha-syn, while more than 90% of peripheral erythrocytes expressed alpha-syn. Nonetheless, alpha-syn null mice exhibited apparently no phenotypic changes in erythroid cells as was the case in their brains, suggesting that there might be underlying some redundant mechanisms. Together with previous reports showing the expression of alpha-syn in lymphocytes and platelets, the present finding supports a contention that alpha-syn might play some important functions in hematopoietic system.
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PMID:Expression of alpha-synuclein, a presynaptic protein implicated in Parkinson's disease, in erythropoietic lineage. 1747 20

The transcription of antioxidant response element (ARE)-containing cytoprotective genes has been proposed as a means to combat oxidative stress-related disorders, such as cancer and Parkinson's disease. Transactivation of the ARE requires the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Cellular levels of Nrf2 protein are regulated by the Kelch-like ECH-associated protein 1 (Keap1), a substrate adaptor protein for the ubiquitin ligase machinery and subsequent proteasomal degradation. Recently, detailed studies have elucidated the structure and interactions of the Keap1-containing ubiquitin ligase complex. Here, we propose that small molecule modulation of Keap1 protein:protein interactions may permit Nrf2's nuclear accumulation and the transcription of ARE-dependent genes to enhance cellular resistance to oxidative insult.
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PMID:Disruption of the Keap1-containing ubiquitination complex as an antioxidant therapy. 1750 29

Oxidative stress is central to neuronal damage in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. In consequence, activation of the cerebral oxidative stress defence is considered as a promising strategy of therapeutic intervention. Here we demonstrate that the flavone luteolin confers neuroprotection against oxidative stress via activation of the nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor central to the maintenance of the cellular redox homeostasis. Luteolin protects rat neural PC12 and glial C6 cells from N-methyl-4-phenyl-pyridinium (MPP+) induced toxicity in vitro and effectively activates Nrf2 as shown by ARE-reporter gene assays. This protection critically depends on the activation of Nrf2 since downregulation of Nrf2 by shRNA completely abrogates the protection of luteolin in vitro. Furthermore, the neuroprotective effect of luteolin is abolished by the inhibition of the luteolin-induced ERK1/2-activation. Our results highlight the relevance of Nrf2 for neural cell survival conferred by flavones. In particular, we identified luteolin as a promising lead for the search of orally available, blood brain barrier permeable compounds to support the therapy of neurodegenerative disorders.
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PMID:Luteolin protects rat PC12 and C6 cells against MPP+ induced toxicity via an ERK dependent Keap1-Nrf2-ARE pathway. 1798 79

Erythropoietin (EPO) was first identified as a hematopoietic cytokine that stimulates proliferation and differentiation of erythroid progenitor cells and was approved by the Food and Drug Administration as a treatment for chronic renal disease patients with anemia. In neural tissues, EPO is working via EPO receptors and induces non-hematopoietic effects. Recent studies have demonstrated that EPO exerts therapeutic potentials on neurological disorders such as ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and Parkinson's disease. EPO treatment has been shown to reduce the ischemic infarct and hemorrhage volume, decrease neuronal death including apoptosis, and improve survival rates in animal models. The mechanism of EPO action in neurological disorders involves neuroprotection and promotion of neurogenesis and angiogenesis. Clinical trials of EPO treatments in neurological diseases have accumulated positive results. In stroke patients, EPO treatment may reduce infarct volume and improve functional outcomes. EPO administration has proven safe in animal studies and adult human patients, although safety and efficacy data in neonates and infants are incomplete and long-term multi-center patient evaluations are necessary. Available information suggests that EPO is a promising therapeutic drug for the treatment of neurological diseases.
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PMID:Therapeutic strategy of erythropoietin in neurological disorders. 1867 7

Parkinson's disease (PD) is a progressive, primarily motor disorder that is characterized by loss of dopaminergic (DA) neurons within the substantia nigra (SN). Cell death in PD has been associated with impaired mitochondrial function and increased oxidative stress. Strategies to reduce the oxidative load in DA cells may be beneficial in slowing the progression of PD. The transcription factor nuclear factor-erythroid 2 (NF-E2) related factor 2 (NRF2) is emerging as a master regulator of antioxidant defense systems, which makes it an attractive target for manipulations that aim to increase cellular resistance to oxidative stress. Peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC1alpha) is a regulator of mitochondrial biogenesis genes that simultaneously upregulates many genes known to protect against oxidative stress. Pgc-1alpha knockout mice show enhanced susceptibility to SN neuronal loss following MPTP exposure, whilst overexpression of Pgc-1alpha appears to protect against oxidative stress in vitro. This makes PGC-1alpha a highly attractive target for neuroprotective therapies in PD. This review will explore the mechanisms behind the induction of NRF2 and PGC-1alpha in response to oxidative stress and identify common pathways that may provide targets for upregulating antioxidant defense programs.
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PMID:Transcribe to survive: transcriptional control of antioxidant defense programs for neuroprotection in Parkinson's disease. 1871 31

In recent years, it has been accepted that oxidative stress is critically involved in the etiopathology of Parkinson's disease (PD) and as a result new therapeutic targets for reduction of oxidant injury and neuroprotection can be defined. Here we discuss the potential use of the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), as a pharmacological target for neuroprotective therapy in PD. Data generated by various groups indicate that Nrf2 induces the expression of a group of cytoprotective, antixenobiotic and antioxidant enzymes that include heme oxygenase-1, NAD(P)H:quinone oxidoreductase and enzymes of glutathione (GSH) metabolism such as gamma-glutamyl cysteine ligase, GSH transferases and so on. Two strategies are known to increase Nrf2 transcriptional activity in PD: i) use of certain catechol-derived quinones for selective inhibition of the Nrf2 repressor Kelch-like ECH-associated protein to increase of Nrf2 protein levels; and ii) use of glycogen synthase kinase 3beta inhibitors to maintain high protein and activity levels of Nrf2 in the nucleus. This review provides a rationale for drug design of appropriate molecules that might endorse a neuroprotective strategy to PD on the basis of attenuation of oxidative stress.
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PMID:The transcription factor Nrf2 as a new therapeutic target in Parkinson's disease. 1923 54

It was shown that high levels of alpha-synuclein in substantia nigra are essential in pathogenesis of Parkinson disease (PD), and SNCA expression in neurons is controlled by GATA-2 transcription factor, which plays also crucial role in central nervous system development, and erythroid cells differentiation. Recently, significant association of two GATA2 SNPs with early-onset coronary artery disease has been presented. In this case-control study we tested a hypothesis that polymorphism of GATA2 gene may be associated with sporadic PD. Five tag SNPs within GATA2 gene (rs2860228:G > A, rs2335052:G > A, rs11717152:A > C, rs2713604:G > A, and rs3803:C > T) were investigated in 368 PD patients and 349 controls of Caucasian origin from Poland. We did not find any significant differences in the GATA2 allele and genotype frequencies between PD cases and controls, for individual SNPs, neither in haplotype analysis. Elevated frequency of rs3803T allele was observed in early-onset PD patients (vs. controls and vs. late-onset PD), but this difference was not significant (0.05 < p < 0.1). We conclude that GATA2 polymorphism is not an important risk factor for sporadic PD in Caucasians.
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PMID:Association study of GATA-2 transcription factor gene (GATA2) polymorphism and Parkinson's disease. 1986 73

The antioxidant enzyme manganese superoxide dismutase (SOD2) serves as the primary defense against mitochondrial superoxide. Impaired SOD2 activity in murine hematopoietic cells affects erythroid development, resulting in anemia characterized by intra-mitochondrial iron deposition, reticulocytosis and shortened red cell life span. Gene expression profiling of normal and SOD2 deficient erythroblasts identified the Parkinson's disease locus DJ-1 (Park7) as a differentially expressed transcript. To investigate the role of DJ-1 in hematopoietic cell development and protection against oxidative stress caused by Sod2 loss, we evaluated red cell parameters, reticulocyte count, red cell turnover and reactive oxygen species production in DJ-1 knockout animals and chimeric animals lacking both SOD2 and DJ-1 in hematopoietic cells generated by fetal liver transplantation. We also investigated DJ-1 protein expression in primary murine erythroid and erythroleukemia cells (MEL). Loss of DJ-1 exacerbates the phenotype of SOD2 deficiency, increasing reticulocyte count and decreasing red cell survival. Using MEL cells, we show that DJ-1 is up-regulated at the protein level during erythroid differentiation. These results indicate that DJ-1 plays a physiologic role in protection of erythroid cells from oxidant damage, a function unmasked in the context of oxidative stress.
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PMID:The familial Parkinson's disease gene DJ-1 (PARK7) is expressed in red cells and plays a role in protection against oxidative damage. 2080 May 16


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