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)

The multi-drug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette (ABC) superfamily of membrane transporters. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multi-drug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of various types of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and indicated that a single nucleotide polymorphism (SNP), C3435T in exon 26, which caused no amino acid change, was associated with the duodenal expression of MDR1 and thereby the plasma concentrations of digoxin after oral administration. Interethnic differences in genotype frequencies of C3435T have been clarified, and, at present, a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on the effects of C3435T on MDR1 expression and function in the tissues, and also on the pharmacokinetics and pharmacodynamics have been performed around the world; however, there are still discrepancies in the results, suggesting that the haplotype analysis of the gene should be included instead of SNP detection, and the design of clinical trials must be carefully planned to avoid misinterpretations. A polymorphism of C3435T is also reported to be a risk factor for a certain class of diseases such as the inflammatory bowel diseases, Parkinson's disease and renal epithelial tumor, and this might also be explained by the effects on MDR1 expression and function. In this review, the latest reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping.
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PMID:Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs. 1283 20

alpha-Synuclein is a presynaptic protein that accumulates abnormally in Lewy bodies of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Its physiological function and role in neuronal death remain poorly understood. Recent immunohistochemical studies suggest that cell cycle-related phenomena may play a role in the pathogenesis of Alzheimer's disease and perhaps other neurodegenerative disorders. In this investigation, we examined the effects of alpha-synuclein expression levels on cell cycle indices in PC12 cells engineered to conditionally induce alpha-synuclein expression upon withdrawal of doxycycline. Over-expression of alpha-synuclein resulted in enhanced proliferation rate and enrichment of cells in the S phase of the cell cycle. This was associated with increased accumulation of the mitotic factor cyclin B and down-regulation of the tumor suppressor retinoblastoma 2. Additionally, ERK1/2, key molecules in proliferation signaling, were highly phosphorylated. Immunohistochemical studies on postmortem brains revealed intense cyclin B immunoreactivity in Lewy bodies in cases with DLB and to a lesser extent in PD. We propose that elevated expression of alpha-synuclein causes changes in cell cycle regulators through ERK activation leading to apoptosis of postmitotic neurons. These changes in cell cycle proteins are also associated with ectopic expression of cyclin B in Lewy bodies.
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PMID:Cell cycle aberrations by alpha-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies. 1288 76

Eukaryotic plasmid vectors encoding the tyrosine hydroxylase (TH) gene and GTP cyclohydrolase-1 (GCH) gene were constructed and introduced into immortalized fibroblasts obtained from SV40 large antigen (LT(AG)) transformed rat primary fibroblasts. TH and GCH positive clones were selected and identified by immunohistochemistry and RT-PCR, respectively. Hemi-parkinsonian rats created using 6-hydroxydopamine (6-OHDA) were used to assess the therapeutic effect created by the co-implantation of immortalized fibroblasts genetically modified by TH or GCH genes. Animal behavior was significantly improved two weeks following implantation and behavioral correction was maintained for over 14 weeks. Behavioral improvement was paralleled by exogenous TH gene expression, identified by TH immunohistochemistry and RT-PCR analyses. The transplanted cells survived for at least 38 weeks as demonstrated by fibronectin immunohistochemical staining. Tumor formation or host reaction was not seen, although TH expression was negative for 20 weeks after the implantation. This work demonstrates that the co-transplantation of immortalized fibroblasts genetically modified by TH and GCH genes may be developed as a valuable approach to the treatment of Parkinson's disease.
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PMID:Behavioral correction of Parkinsonian rats following the transplantation of immortalized fibroblasts genetically modified with TH and GCH genes. 1291 73

We report the case of a 62-year-old woman with parkinson's disease and depression. Her symptoms included episodes of flushing, palpitations and hypertension, giving rise to the suspicion of the existence of a phaeochromocytoma. The levels of adrenaline and vanillymandelic acid in the urine were moderately elevated, the noradrenaline level was high- normal. Upon further examination, there was no evidence of a phaeochromocytoma or a carcinoid tumor. In the literature, there are reports of pseudophaeochromocytoma in patients receiving levodopa. Elevated levels of catecholamins and their metabolites can be caused by the metabolic process of levodopa and levodopa can influence the outcome of laboratory tests. The patient's depression resolved and the flushing disappeared after treatment with antidepressants and after changing the Parkinson regime.
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PMID:[Pseudophaeochromocytoma in a Patient with Parkinson's Disease and Depression] 1313 Mar 38

We report the case of a 62-year-old woman with parkinson's disease and depression. Her symptoms included episodes of flushing, palpitations and hypertension, giving rise to the suspicion of the existence of a phaeochromocytoma. The levels of adrenaline and vanillymandelic acid in the urine were moderately elevated, the noradrenaline level was high-normal. Upon further examination, there was no evidence of a phaeochromocytoma or a carcinoid tumor. In the literature, there are reports of pseudophaeochromocytoma in patients receiving levodopa. Elevated levels of catecholamins and their metabolites can be caused by the metabolic process of levodopa and levodopa can influence the outcome of laboratory tests. The patient's depression resolved and the flushing disappeared after treatment with antidepressants and after changing the Parkinson regime.
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PMID:[Pseudopheochromocytoma in Parkinson disease and depression]. 1450 40

Neuronal ubiquitin C-terminal hydrolase (UCH-L1) has been linked to Parkinson's disease (PD), the progression of certain nonneuronal tumors, and neuropathic pain. Certain lung tumor-derived cell lines express UCH-L1 but it is not expressed in normal lung tissue, suggesting that this enzyme plays a role in tumor progression, either as a trigger or as a response. Small-molecule inhibitors of UCH-L1 would be helpful in distinguishing between these scenarios. By utilizing high-throughput screening (HTS) to find inhibitors and traditional medicinal chemistry to optimize their affinity and specificity, we have identified a class of isatin O-acyl oximes that selectively inhibit UCH-L1 as compared to its systemic isoform, UCH-L3. Three representatives of this class (30, 50, 51) have IC(50) values of 0.80-0.94 micro M for UCH-L1 and 17-25 micro M for UCH-L3. The K(i) of 30 toward UCH-L1 is 0.40 micro M and inhibition is reversible, competitive, and active site directed. Two isatin oxime inhibitors increased proliferation of the H1299 lung tumor cell line but had no effect on a lung tumor line that does not express UCH-L1. Inhibition of UCH-L1 expression in the H1299 cell line using RNAi had a similar proproliferative effect, suggesting that the UCH-L1 enzymatic activity is antiproliferative and that UCH-L1 expression may be a response to tumor growth. The molecular mechanism of this response remains to be determined.
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PMID:Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line. 1452 54

The cloning and characterization of the common fragile site (CFS) FRA6E (6q26) identified Parkin, the gene involved in the pathogenesis of many cases of juvenile, early-onset and, rarely, late-onset Parkinson's disease, as the third large gene to be localized within a large CFS. Initial analyses of Parkin indicated that in addition to playing a role in Parkinson's disease, it might also be involved in the development and/or progression of ovarian cancer. These analyses also indicated striking similarities among the large CFS-locus genes: fragile histidine triad gene (FHIT; 3p14.2), WW domain-containing oxidoreductase gene (WWOX; 16q23), and Parkin (6q26). Analyses of FHIT and WWOX in a variety of different cancer types have identified the presence of alternative transcripts with whole exon deletions. Interestingly, various whole exon duplications and deletions have been identified for Parkin in juvenile and early-onset Parkinson's patients. Therefore, we performed mutational/exon rearrangement analysis of Parkin in ovarian cancer cell lines and primary tumors. Four (66.7%) cell lines and four (18.2%) primary tumors were identified as being heterozygous for the duplication or deletion of a Parkin exon. Additionally, three of 23 (13.0%) nonovarian tumor-derived cell lines were also identified as having a duplication or deletion of one or more Parkin exons. Analysis of Parkin protein expression with antibodies revealed that most of the ovarian cancer cell lines and primary tumors had diminished or absent Parkin expression. While functional analyses have not yet been performed for Parkin, these data suggest that like FHIT and WWOX, Parkin may represent a tumor suppressor gene.
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PMID:Alterations in the common fragile site gene Parkin in ovarian and other cancers. 1461 60

Parkin is a protein that when mutated leads to an inherited form of Parkinson's disease. Under normal conditions, this molecule has multiple functions in different cell types, including protein degradation and tumor suppression. To understand the relationship between parkin and circulating corticosteroid hormones, we studied the long-term depletion of corticosterone due to bilateral adrenalectomy in rats. We show that adrenalectomy deletes the expected expression of nuclear parkin in hippocampal neurons. Notably, the effect of adrenalectomy on parkin was prevented by corticosterone hormone replacement therapy. This finding suggests that adrenal hormones may be critical in sustaining parkin ubiquitinating activity in the rat hippocampus.
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PMID:Regulation of hippocampal parkin protein by corticosteroids. 1466 85

It is well documented that disturbances in mitochondrial function are associated with rare childhood disorders and possibly with many common diseases of ageing, such as Parkinson's disease and dementia. There has also been increasing evidence linking mitochondrial dysfunction with tumorigenesis. Recently, heterozygous germline mutations in two enzymes of the Krebs tricarboxylic acid cycle (TCA cycle) have been shown to predispose individuals to tumours. The two enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are ubiquitously expressed, playing a vital role in adenosine triphosphate (ATP) production through the mitochondrial respiratory chain. Germline mutations in FH are associated with leiomyomatosis and renal cell carcinoma, whilst SDH mutations are associated with predisposition to paraganglioma (PGL) and phaeochromocytoma (PCC). At present, there are few data to explain the pathway(s) involved in this predisposition to neoplasia through TCA cycle defects. We shall review the mechanisms by which mutations in FH and SDH might play a role in tumorigenesis. These include pseudo-hypoxia, mitochondrial dysfunction and impaired apoptosis, oxidative stress and anabolic drive. All of these mechanisms are currently poorly defined. To date, FH and SDH mutations have not been reported in non-familial leiomyomata, renal cancers, PCCs or PGLs. It remains entirely possible, however, that the underlying mechanisms of tumorigenesis in these sporadic tumours are the same as those in the Mendelian syndromes.
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PMID:The TCA cycle and tumorigenesis: the examples of fumarate hydratase and succinate dehydrogenase. 1470 72

It is well known that neuropathy, myelopathy, and arthropathy are specific adverse effects induced by paclitaxel administration. Parkinson's disease is neural degenerative disease, and the influence of paclitaxel administration on patients with Parkinson's disease is unknown. We have successfully treated an ovarian cancer patient with Parkinson's disease by paclitaxel/CBDCA combined chemotherapy after surgery. The patient was a 57-year-old woman with solid and cystic ovarian tumor. Among the tumor markers CA125, CA19-9, and SLX, only SLX was elevated. We operated and made a pathological diagnosis of the ovarian tumor as clear cell adenocarcinoma (FIGO stage Ic). After surgery, the patient was treated with paclitaxel (260 mg [175 mg/m2]) and CBDCA (600 mg [AUC = 5]) combined chemotherapy for 5 courses. Her status is complete remission. During chemotherapy, she had felt the decreased efficacy of her Parkinson's disease medication. We could continue chemotherapy by increasing the dose of the Parkinson's drug. There is only one case report on the influence of paclitaxel on Parkinson's disease, in which the course was similar to the present case.
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PMID:[A case of ovarian cancer with Parkinson's disease treated by combined chemotherapy with paclitaxel and carboplatin followed by surgery]. 1471 77


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