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 nature of Lewy bodies (LBs) in the brain stem and cerebral cortex in five cases of diffuse Lewy body disease and one case of Parkinson's disease with dementia were investigated immunocytochemically with various antibodies to cytoskeletal proteins, paired helical filaments (PHF) and ubiquitin. Antibodies to 200-kDa component of neurofilament, tau and PHF showed no significant reactions with most of LBs. Antibodies to high-molecular weight microtubule-associated proteins (HMWMAPs) moderately stained the periphery of a few of LBs. A monoclonal antibody to PHF (DF2) which recognizes ubiquitin, and polyclonal antibodies to ubiquitin immunostained virtually all of the typical and cortical LBs as intensely as Alzheimer's neurofibrillary tangles and senile plaque neurites: the periphery of LBs was darkly stained, whereas the central core of typical LBs and central zone of cortical LBs were less intensely stained or remained unstained. Immunoelectron microscopy of the LBs with DF2 revealed that immune reaction products were located on the filaments exclusively in the periphery of LBs, but not on those in the center. These findings suggest that both types of LBs are immunocytochemically indistinguishable despite some structural differences, and that peripherally located filaments in LBs are tagged with ubiquitin, an element required for the ATP-dependent proteolysis system in the cell. Antibodies to ubiquitin are the most useful marker of LBs ever known.
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PMID:Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study. 336 59

1. Human blood platelets have been shown to take up dopamine by an energy-dependent, saturable process that is inhibited by 5-hydroxytryptamine (5-HT), desipramine and other drugs.2. Platelets from parkinsonian subjects receiving oral L-DOPA also took up dopamine.3. When the responses of normal and parkinsonian platelets were compared, the parkinsonian cells showed the following differences: increased affinity for the dopamine transport process; decreased equilibrium concentrations of dopamine after incubation for 90 min, and greater efflux of dopamine from loaded platelets during a 10 min incubation.4. There were no differences in the uptake of 5-HT by parkinsonian platelets, but endogenous 5-HT was significantly reduced; ATP was normal.5. In two out of three samples of platelets from parkinsonian subjects, traces of a dopamine-like substance were detected, but this finding requires confirmation.6. If the platelet is a valid model for dopaminergic brain neurones, then the results described would suggest that dopamine uptake and storage may be abnormal in brain neurones in Parkinson's disease.
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PMID:Accumulation of dopamine by blood platelets from normal subjects and parkinsonian patients under treatment with L-DOPA. 548 51

We discuss the etiology and pathogenesis of Parkinson's disease (PD). Our group and others have found a decrease in complex I of the mitochondrial electron transfer complex in the substantia nigra of patients with PD; in addition, we reported loss of the alpha-ketoglutarate dehydrogenase complex (KGDHC) in the substantia nigra. Dual loss of complex I and the KGDHC will deleteriously affect the electron transport and ATP synthesis; we believe that energy crisis is the most important mechanism of nigral cell death in PD. Oxidative stress has also been implicated as an important contributor to nigral cell death in PD, but we believe that oxidative stress is a secondary phenomenon to respiratory failure, because respiratory failure will increase oxygen free-radical formation and consume glutathione. The primary cause of mitochondrial respiratory failure has not been elucidated yet, but additive effect of environmental neurotoxins in genetically predisposed persons appears to be the most likely possibility.
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PMID:Role of mitochondria in the etiology and pathogenesis of Parkinson's disease. 759 19

The activity of complex I of the respiratory chain is decreased in the substantia nigra of patients with Parkinson's disease (PD) but the presence of this defect in skeletal muscle is controversial. Therefore, the mitochondrial function of skeletal muscle in patients with PD was investigated in vivo using 31P magnetic resonance spectroscopy. Results from 7 PD patients, 11 age matched controls and 9 mitochondrial myopathy patients with proven complex I deficiency were obtained from finger flexor muscle at rest, during exercise and in recovery from exercise. In resting muscle, the patients with mitochondrial myopathy showed a low PCr/ATP ratio, a low phosphorylation potential, a high P(i)/PCr ratio and a high calculated free [ADP]. During exercise, stores of high energy phosphate were depleted more rapidly than normal, while in recovery, the concentration of phosphocreatine and free ADP returned to pre-exercise values more slowly than normal. In contrast, the patients with PD were not significantly different from normal for any of these variables, and no abnormality of muscle energetics was detected. Three of the PD patients also had mitochondrial function assessed biochemically in muscle biopsies. No respiratory chain defect was identified in any of these patients by polarography or enzyme analysis when compared with age-matched controls. These results suggest that skeletal muscle is not a suitable tissue for the investigation and identification of the biochemical basis of the nigral complex I deficiency in PD.
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PMID:A 31P magnetic resonance spectroscopy study of mitochondrial function in skeletal muscle of patients with Parkinson's disease. 796 92

The ATP-ubiquitin-dependent proteolytic pathway (ubiquitin pathway) is believed to be involved in the formation of various neuronal inclusion bodies including Lewy bodies (LBs), a pathological hallmark of Parkinson disease and diffuse Lewy body disease (DLBD). Since multicatalytic proteinase (MCP) is involved in the ubiquitin pathway, an investigation of whether MCP is involved in neuronal inclusion bodies would provide a clue to the mechanism underlying the formation of neuronal inclusion bodies as well as to the pathogenesis of degenerative neurological disorders. In this study, we investigated detailed immunolocalization of MCP in LBs in DLBD brains using light and electron microscopy. We raised three different monoclonal antibodies against purified human MCP. Each of them recognized different sets of MCP subunits on Western blotting. Immunohistochemically, anti-MCP antibodies recognized all ubiquitin-positive cortical LBs in situ as well as those isolated from frozen DLBD cortices, suggesting that MCP is present in LBs as a whole molecule exhibiting protease activity. In electron microscopy, MCP immunoreactivity (MCP-IR) was exclusively localized on a characteristic oval structure with an approximate diameter of 100 nm. This structure was distributed throughout the LBs and was devoid of ubiquitin immunoreactivity. Treatment of isolated LBs with 2% SDS, but not with 0.5% Triton X-100, removed this structure from LBs in which fibrous materials predominated. Ubiquitin immunoreactivity was also decreased in isolated LBs treated with 2% SDS, suggesting that the fibrous structures in LBs were not ubiquitinated in situ. Thus, it is suggested that LBs are subjected to a proteolytic process in which MCP plays a role via processing of specific components of LBs.
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PMID:Multicatalytic proteinase is associated with characteristic oval structures in cortical Lewy bodies: an immunocytochemical study with light and electron microscopy. 802 94

In human brain, [3H]glibenclamide binds with high affinity (KD about 3.5 nM) to sulfonylurea binding sites which are associated with ATP-sensitive potassium (KATP) channels. Regarding to the important neuromodulatory action of KATP channels in some neuronal populations, sulfonylurea binding sites were measured in several cortical areas (frontal and temporal cortex, hippocampus) and striatum (caudate nucleus and putamen) in controls and patients with Parkinson's disease or progressive supranuclear palsy. There was no modification of [3H]glibenclamide specific binding in the cerebral regions studied in both pathologies. These results indicate that KATP channels do not seem to be involved in the pathophysiology of these degenerative processes. Brain samples from five patients with Huntington's disease were studied. A small decrease in sulfonylurea binding sites was measured in the frontal cortex, caudate nucleus and putamen which could be due to the loss of either neurons or nerve endings. This low decrease contrasts with the dramatic diminution of many other markers associated with the profound striatal degeneration occurring in Huntington's disease.
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PMID:Sulfonylurea binding sites in normal human brain and in Parkinson's disease, progressive supranuclear palsy and Huntington's disease. 803 96

The in vivo effects of dopamine-derived alkaloids, 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines, salsolinols, and their N-methylated derivatives on a dopaminergic cell model, clonal rat pheochromocytoma PC12h cells, were examined by culture in the presence of various concentrations of the agents. The effects were evaluated in comparison with those by 1,2,3,4-tetrahydroisoquinoline and its N-methylated derivatives. Among 1,2,3,4-tetrahydroisoquinolines, only N-methylisoquinolinium ion had cytotoxic effect on PC12h cells. In general, 6,7-dihydroxyisoquinolines had more potent cytotoxic effect than N-methylisoquinolinium ion, and they reduced protein amounts of PC12h cells at 100 microM and 1 mM concentration. The specific activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis, decreased with these isoquinolines at concentrations lower than those required to reduce the protein amount. The toxicity of N-methylated derivatives seems to be more potent than non-methylated isoquinolines. Salsolinols were proved to be accumulated in the mitochondrial fraction of the cells after 3 days in culture. N-methyl-1,2,3,4-tetrahydroisoquinoline depleted ATP from PC12h cells and it was prevented by preincubation with an inhibitor of type-A monoamine oxidase, clorgyline. These results indicate that N-methylated and oxidized derivatives of dopamine-derived alkaloids may be potent dopaminergic neurotoxins similar to 1-methyl-4-phenylpyridinium ion in the human brain and may induce Parkinson's disease after long years of accumulation.
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PMID:Cytotoxicity of dopamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines. 809 79

N-Methylated beta-carbolinium cations that can form in vivo from environmental or endogenous beta-carbolines are putative neurotoxic factors in Parkinson's disease. The cytotoxicities of 11 N-methylated beta-carbolinium cations and N-methyl-4-phenylpyridinium cation (MPP+), the experimental parkinsonian neurotoxicant which the carbolinium cations structurally resemble, were examined using rat pheochromocytoma (PC12) cells cultured in "low energy" N-5 medium; cell death was estimated by released lactate dehydrogenase activity and viable cell protein. Of the eight N2-monomethylated beta-carbolinium cations utilized, only 2-methyl-harmalinium (harmaline-2-methiodide) was as cytotoxic as MPP+. Also, three N2(beta), N9(indole)-dimethylated beta-carbolinium cations displayed cytotoxic effects, with the simplest, 2,9-dimethylnorharmanium, approaching the effectiveness of MPP+ in PC12 cells cultured in N-5 medium. However, when PC12 cells grown in higher energy Dulbecco's modified Eagle's medium were utilized with selected effective cations, it was observed that the cultures were relatively resistant to MPP+ and 2,9-dimethylnorharmanium, but remained vulnerable to 2-methylharmalinium. The results are interpreted to mean that different cytotoxic mechanisms exist for the two most potent beta-carbolinium cations--namely, a mechanism for the 2,9-dimethyl-beta-carbolinium species that, as with MPP+, is conditional on mitochondrial ATP depletion, but a different (or additional) mechanism for 2-methylharmalinium that is independent of mitochondrial inhibition. The possible accumulation of these cytotoxic cations in Parkinson's disease is discussed in the context of these findings.
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PMID:Differential cytotoxicities of N-methyl-beta-carbolinium analogues of MPP+ in PC12 cells: insights into potential neurotoxicants in Parkinson's disease. 813 78

The biochemical process underlying Parkinson's disease is dopamine cell death of the nigrostriatal system. The age-dependent cell death is now proposed to be elicited by the formation of free hydroxy radicals which are formed from hydrogen peroxide, a product of oxidation of dopamine by monoamine oxidase, especially type B. The potent neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, was found to induce cell death by an energy crisis or oxidative stress in dopamine neurons. Other endogenous mammalian neurotoxins, monoamine-derived 1,2,3,4-tetrahydroisoquinolines and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines, have been proposed as factors accelerating dopamine cell death. N-methylated isoquinolines were found to be oxidized by monoamine oxidase, and hydroxy radicals were found to be produced by this reaction. In addition, by incubation with the N-methylated isoquinolines, ATP was depleted from a dopaminergic cell model, clonal rat pheochromocytoma PC12h cells. ATP depletion could be protected by pretreatment of the cells with monoamine oxidase inhibitors. These results suggest that oxidation of neurotoxic isoquinolines is directly involved in the oxidative stress to induce the cell death of dopamine neurons. On the other hand, 1-methyl-1,2,3,4-tetrahydroisoquinoline and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline were found to inhibit the activity of monoamine oxidase, indicating that they may be neuroprotective agents in the brain. The involvement of monoamine oxidase is discussed in relation to the pathogenesis of Parkinson's disease.
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PMID:Type B monoamine oxidase and neurotoxins. 837 30

L-dopa, the major treatment for Parkinson's disease (PD), depletes S-adenosyl-L-methionine (SAM). Since SAM causes PD-like symptoms in rodents, the decreased efficacy of chronic L-dopa administered to PD patients may result from a rebound increase in SAM via methionine adenosyl transferase (MAT), which produces SAM from methionine and ATP. This was tested by administering intraperitoneally saline, or L-dopa to mice and assaying for brain MAT activity. As compared to controls, L-dopa (100 mg/kg) treatments of 1 and 2 times per day for 4 days did not significantly increase MAT activity. However, treatments of 3 times per day for 4 and 8 days did significantly increase the activity of MAT by 21.38% and 28.37%, respectively. These results show that short interval, chronic L-dopa treatments significantly increases MAT activity, which increases the production of SAM. SAM may physiologically antagonize the effects of L-dopa and biochemically decrease the concentrations of L-dopa and dopamine. Thus, an increase in MAT may be related to the decreased efficacy of chronic L-dopa therapy in PD.
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PMID:The effects of L-dopa on the activity of methionine adenosyltransferase: relevance to L-dopa therapy and tolerance. 847 1


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