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)

Manganese toxicity has been associated with clinical symptoms of neurotoxicity which are similar to the symptoms observed in Parkinson's disease. Earlier reports indicated that reactive microglia was present in the substantia nigra of patients with Parkinson's disease. Using N9 microglial cells, the current study was designed to determine whether high levels of manganese were associated with microglial activation. Results indicated that manganese significantly increased the bacterial lipopolysaccharide-induced nitric oxide production. This potent activity of manganese was not shared by other transition metals tested, including iron, cobalt, nickel, copper and zinc. Immunohistochemical staining and Western blot analysis indicated that manganese increased the cellular production of inducible nitric oxide synthase. Northern blot analysis indicated that manganese likely increased iNOS gene transcription since this agent increased the mRNA level of the inducible nitric oxide synthase. In contrast to other transition metals tested, manganese did not appear to be cytotoxic to microglial cells. These results suggested that manganese could induce sustained production of neurotoxic nitric oxide by activated microglial cells, which might cause detrimental consequences to surrounding neurons.
Brain Res Mol Brain Res 1999 May 07
PMID:Manganese potentiates nitric oxide production by microglia. 1032 Jul 80

The identification of novel factors that promote neuronal survival could have profound effects on developing new therapeutics for neurodegenerative disorders. Glial cell line-derived neurotrophic factor (GDNF) is a novel protein purified and cloned based on its marked ability to promote dopaminergic neuronal function. GDNF, now known to be the first identified member of a family of factors, signals through the previously known receptor tyrosine kinase, Ret. Unlike most ligands for receptor tyrosine kinases, GDNF does not bind and activate Ret directly, but requires the presence of GPI-linked coreceptors. There are several coreceptors with differing affinities for the GDNF family members. The profile of coreceptors in a cell may determine which factor preferentially activates Ret. In vivo differences in localization of the GDNF family members, its coreceptors and Ret suggest this ligand/receptor interaction has extensive and multiple functions in the CNS as well as in peripheral tissues. GDNF promotes survival of several neuronal populations both in vitro and in vivo. Dopaminergic neuronal survival and function are preserved by GDNF in vivo when challenged by the toxins MPTP and 6-hydroxydopamine. Furthermore, GDNF improves the symptoms of pharmacologically induced Parkinson's disease in monkeys. Several motor neuron populations isolated in vitro are also rescued by GDNF. In vivo, GDNF protects these neurons from programmed cell death associated with development and death induced by neuronal transection. These experiments suggest that GDNF may provide significant therapeutic opportunities in several neurodegenerative disorders.
Mol Neurobiol 1999 Feb
PMID:GDNF: a novel factor with therapeutic potential for neurodegenerative disorders. 1032 71

Rat embryonic d 14 (E14) mesencephalic cells, 2.5% of which are glioblasts, were incubated in medium containing 10% of fetal bovine serum for 12 h and subsequently expanded in a serum-free medium using basic fibroblast growth factor (bFGF) as the mitogen. On a single occasion, after more than 15 d in culture, several islets of proliferating, glial-like cells were observed in one dish. The cells, when isolated and passaged, proliferated rapidly in either a serum-free or serum-containing growth medium. Subsequent immunocytochemical analysis showed that they stained positive for GFAP and vimentin, and negative for A2B5, O4, GalC, and MAP2. Serum-free conditioned medium (CM) prepared from these cells caused a fivefold increase in survival and promoted neuritic expansion of E14 mesencephalic dopaminergic neurons in culture. These actions are similar to those exerted by CM derived from primary, mesencephalic type-1 astrocytes. The pattern of expression of the region-selective genes; wnt-1, en-1, sis showed that 70% of the cells were heteroploid, and of these, 50% were tetraploid. No apparent decline in proliferative capacity has been observed after 25 passages. The properties of this cell line, named ventral mesencephalic cell line one (VMCL1), are consistent with those of an immortalized, type-1 astrocyte. The mesencephalic origin of the cell line, and the pattern and potency of the neurotrophic activity exerted by the CM, strongly suggest that the neurotrophic factor(s) identified are novel, and will likely be strong candidates with clinical utility for the treatment of Parkinson's disease.
J Mol Neurosci 1998 Dec
PMID:An immortalized, type-1 astrocyte of mesencephalic origin source of a dopaminergic neurotrophic factor. 1034 91

In the present study we analyzed the temporo-spatial expression pattern of basic fibroblast growth factor (bFGF) and transforming growth factor beta 2 (TGFbeta2) in embryonic dopaminergic transplants in the 6-hydroxydopamine rat model of Parkinson's disease. The grafts differentiated for 1, 2, 4 and 8 weeks, respectively and were then analyzed using antibodies directed against tyrosine hydroxylase, bFGF and TGFbeta2. At all time points investigated, grafts contained tyrosine hydroxylase immunoreactive neurons. One week after transplantation the grafts displayed no immunoreactivity for bFGF and TGFbeta2. In more mature grafts (starting at 2 weeks post transplantation) bFGF and TGFbeta2 immunoreactivity became detectable within the graft and at the graft-host interface but was restricted only to astrocytes. In the striatum surrounding the graft, a transient increase of TGFbeta2 immunoreactive astrocytic processes was observed between 1 and 2 weeks after transplantation. This temporo-spatial expression pattern of TGFbeta2 immunoreactive astrocytes suggests that the upregulation of TGFbeta2 is more likely due to the trauma imposed by the transplantation procedure than to an intrinsic differentiation program. Lack of both bFGF and TGFbeta2 expression in grafted dopaminergic neurons compared to their normal expression in the adult rat substantia nigra indicates that these transplanted neurons do not develop their complete physiological phenotype. Together with the observed deficiency in astrocytic bFGF early after grafting this may be responsible for the poor survival of grafted embryonic dopaminergic cells.
Brain Res Mol Brain Res 1999 May 21
PMID:Temporo-spatial expression of bFGF and TGFbeta2 in embryonic dopaminergic grafts in a rat model of Parkinson's disease. 1035 Jun 37

Considerable evidence implicates the involvement of mitochondrial dysfunction in neurodegenerative diseases. 6OHDA is a mitochondrial complex I inhibitor which is frequently used to model Parkinson's disease-like cell loss. We investigated the cell death pathways triggered by 6OHDA in PC12 and P19 cells with a view to shedding light on the molecular basis of Parkinson's disease. We found that 6OHDA triggered mostly necrosis and less than 5% apoptosis in PC12 cells, whereas 6OHDA-induced death in P19 cells was apoptotic. While desipramine, a dopamine uptake blocker, attenuated 6OHDA-induced apoptosis in PC12 cells, this compound had no effect on the large scale necrotic death. Furthermore, desipramine failed to reduce apoptosis in 6OHDA-treated P19 cells, suggesting that the mechanism of 6OHDA toxicity does not require uptake via the dopamine transporter. As cell death triggered by 6OHDA was not blocked by free radical scavengers or NMDA receptor antagonists, a non-specific extracellular mechanism may be involved.
Brain Res Mol Brain Res 1999 May 21
PMID:The toxicity of 6-hydroxydopamine on PC12 and P19 cells. 1035 Jun 40

Dysfunction of the mitochondrial respiratory chain has been recognised as a cause of human disease for over 30 years. Advances in the past 10 years have led to a better understanding of the genetics and molecular pathogenesis of many of these disorders. Over 100 primary defects in mitochondrial DNA (mtDNA) are now implicated in the pathogenesis of a group of disorders which are collectively known as the mitochondrial encephalomyopathies, and which most frequently involve skeletal muscle and/or the central nervous system. Although impaired oxidative phosphorylation is likely to be the final common pathway leading to the cellular dysfunction associated with such mtDNA mutations, the complex relationship between genotype and phenotype remains largely unexplained. Most of the genes which encode the respiratory chain reside in the nucleus, yet only five nuclear genes have been implicated in human respiratory chain diseases. There is evidence that respiratory chain dysfunction is present in common neurological diseases such as Parkinson's disease and Huntington's disease. The precise cause of this respiratory chain dysfunction and its relationship to the disease process are unclear. This review focuses upon respiratory chain disorders associated with primary defects in mtDNA.
Cell Mol Life Sci 1999 May
PMID:Genetics and molecular pathogenesis of mitochondrial respiratory chain diseases. 1037 58

Catechol-O-methyltransferase (COMT, EC 2.1.1.6) is a ubiquitous enzyme that is crucial to the metabolism of carcinogenic catechols and catecholamines. Regulation of human COMT gene expression may be important in the pathophysiology of various human disorders including estrogen-induced cancers, Parkinson's disease, depression, and hypertension. The gender difference in human COMT activity and variations in rat COMT activity during the estrous cycle led us to explore whether estrogen can regulate human COMT gene transcription. Our Northern analyses showed that physiological concentrations of 17-beta-estradiol (10(-9)-10(-7) M) could decrease human 1. 3-kilobase COMT mRNA levels in MCF-7 cells in a time- and dose-dependent manner through an estrogen receptor-dependent mechanism. Two DNA fragments immediately 5' to the published human COMT gene proximal and distal promoters were cloned. Sequence analyses revealed several half-palindromic estrogen response elements and CCAAT/enhancer binding protein sites. By cotransfecting COMT promoter-chloramphenicol acetyltransferase reporter genes with human estrogen receptor cDNA and pSV-beta-galactosidase plasmids into COS-7 cells, we showed that 17-beta-estradiol could down-regulate chloramphenicol acetyltransferase activities, and COMT promoter activities dose-dependently. Functional deletion analyses of COMT promoters also showed that this estrogenic effect was mediated by a 280 base pair fragment with two putative half-palindromic estrogen response elements in the proximal promoter and a 323-base pair fragment with two putative CCAAT/enhancer binding protein sites in the distal promoter. Our findings provide the first evidence and molecular mechanism for estrogen to inhibit COMT gene transcription, which may shed new insight into the role of estrogen in the pathophysiology of different human disorders.
Mol Pharmacol 1999 Jul
PMID:Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. 1038 81

The central cannabinoid receptor (CB1) mediates the pharmacological activities of cannabis, the endogenous agonist anandamide and several synthetic agonists. The cloning of the human cannabinoid receptor (CNR1) gene facilitates molecular genetic studies in disorders like Gilles de la Tourette syndrome (GTS), obsessive compulsive disorder (OCD), Parkinsons disease, Alzheimers disease or other neuro psychiatric or neurological diseases, which may be predisposed or influenced by mutations or variants in the CNR1 gene. We detected a frequent silent mutation (1359G-->A) in codon 453 (Thr) of the CNR1 gene that turned out to be a common polymorphism in the German population. Allele frequencies of this polymorphism are 0.76 and 0.24, respectively. We developed a simple and rapid polymerase chain reaction (PCR)-based assay by artificial creation of a Msp I restriction site in amplified wild-type DNA (G-allele), which is destroyed by the silent mutation (A-allele). The intragenic CNR1 polymorphism 1359(G/A) should be useful for association studies in neuro psychiatric disorders which may be related to anandamide metabolism disturbances.
Mol Cell Probes 1999 Aug
PMID:A frequent polymorphism in the coding exon of the human cannabinoid receptor (CNR1) gene. 1044 Dec 6

Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features leading to neuronal death in cerebral ischemia, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nitric oxide (NO) alone or in cooperation with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of NO synthase (NOS) inhibitors and mutant mice lacking each NOS isoform have provided evidence for the injurious effects of NO derived from neuronal or inducible isoforms. New neuroprotective strategies have been proposed with selective NOS inhibitors for the neuronal (ARL17477) or the inducible (1400 W) isoforms or with compounds combining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in experimental ischemia-induced acute neuronal damage. The efficacy of these new strategies is well established in acute neuronal injury but remains to be determined in more chronic neurological diseases.
Cell Mol Life Sci 1999 Jul
PMID:Nitric oxide synthases: targets for therapeutic strategies in neurological diseases. 1044 86

Despite being considered the archetypal non-genetic neurological disorder, genetic analysis of Parkinson's disease has shown that there are at least three genetic loci. Furthermore, these analyses have suggested that the phenotype of the pathogenic loci is wider than simple Parkinson's disease and may include Lewy body dementia and some forms of essential tremor. Identification of alpha-synuclein as the first of the loci involved in Parkinson's disease and the identification of this protein in pathological deposits in other disorders has led to the suggestion that it may share pathogenic mechanisms with multiple system atrophy, Alzheimer's disease and prion disease and that these mechanisms are related to a synuclein pathway to cell death. Finally, genetic analysis of the synuclein diseases and the tau diseases may indicate that this synuclein pathway is an alternative to the tau pathway to cell death.
Hum Mol Genet 1999
PMID:The genetics of disorders with synuclein pathology and parkinsonism. 1046 43


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