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)

Two up-to-date known paraoxonase 1 (PON1) polymorphisms (Gln--Arg 191 and Leu--Met 54) affect the hydrolysis of toxic oxons and might intensify effects of pollutants, organophosphates and other environmental chemicals in development of Parkinson's disease (PD). We reported previously that PON1 G1n--Arg 191 polymorphism did not influence on the susceptibility to PD. In the present study we have investigated the PON1 Leu--Met 54 polymorphism in 117 patients with sporadic idiopathic PD. A new approach for Leu--Met 54 polymorphism genotyping has been developed. We have showed the frequency of the Met 54 allele of PON1 to be significantly increased in patients with PD compared with the controls (chi(2)=8.63, df=1, P<0.003). The relative risk of PD in the Met 54 allele carriers has been estimated to be 2.3 fold higher than in homozygotes for the L allele. Moreover it appeared to be even 5.15 higher in the subgroup of patients with early-onset PD. We suggest that the Met 54 allele may be considered to be an independent risk factor for PD. This mutation could probably cause PON1 impaired metabolism of environmental neurotoxins and might be responsible for neurodegeneration.
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PMID:Paraoxonase 1 Met--Leu 54 polymorphism is associated with Parkinson's disease. 1123 53

Levodopa is administered with dopa decarboxylase inhibitors (DDI) to prevent its peripheral degradation. This increases conversion of levodopa to 3-O-methyldopa (3-OMD) by catechol-O-methyltransferase (COMT). S-adenosylmethionine (SAM), which is synthesized from adenosine triphosphate and methionine (MET), serves as methyl donor for this O-metabolisation of levodopa with resulting conversion of SAM to total homocysteine (tHcy) via S-adenosylhomocysteine (SAH). Previous studies showed augmented plasma levels of tHcy in long-term levodopa/DDI-treated patients with Parkinson's disease (PP). Objective of this study was to compare MET, SAM, levodopa, 3-OMD, tHcy and SAH in plasma of 20 levodopa/DDI treated PP and corresponding controls. A significant decrease of MET respectively SAM and an increase of tHcy appeared in PP. SAH with its short half-life did not differ. Levodopa/DDI long-term treatment contributes to altered levels of substrates of the O-methylation cycle in PP.
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PMID:Decrease of methionine and S-adenosylmethionine and increase of homocysteine in treated patients with Parkinson's disease. 1144 84

The prion protein gene was studied in patients with definite or probable Creutzfeldt-Jakob disease (CJD) registered by national CJD units of 6 European countries. The role of genetic factors in CJD was also investigated by comparing the frequencies of a family history of dementia and Parkinson's disease in CJD cases and matched controls. Codon 129 genotype was examined in 337 CJD cases of whom 73.2 p. 100 were homozygous for methionine, 10.9 p. 100 were homozygous for valine and 15.7 p. 100 were heterozygous. The genotype frequencies were not statistically different across countries. Future differences, if any, would constitute a meaningful signal for the surveillance of CJD in Europe. A prion protein gene mutation was found in 14.5 p. 100 of CJD cases; only 40 p. 100 of them had a known family history of CJD. The case-control study showed that positive family histories of dementia and Parkinson's disease were both associated with CJD. Although recall bias is the most likely explanation for this finding, the hypothesis that neurodegenerative diseases might share unknown genetic risk factors can also be considered.
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PMID:Genetic epidemiology of Creutzfeldt-Jakob disease in Europe. 1145 82

High nonphysiological doses of l-dopa are administered to Parkinson's disease (PD) patients, to replenish the depleted dopamine (DA). A large portion of the administered L-dopa and the newly formed DA undergoes methylation by reacting with S-adenosyl-L-methionine (SAM). In the process SAM, as well as L-dopa and DA, is utilized and great demands are placed on the transmethylation system. In this study we investigated whether L-dopa increases the transmethylation process by inducing methionine adenosyl transferase (MAT), the enzyme that produces SAM, and catechol-O-methyl transferase (COMT), the enzyme that transfers the methyl group from SAM to L-dopa and DA. Swiss Webster mice were injected with L-dopa, four times/day, for 1 to 16 days. Brain DA, 3-O-methyldopa (3-OMD), SAM, S-adenosylhomocysteine (SAH), MAT, and COMT were measured following a 24-h withdrawal period. An increase of 264% of brain DA occurred at days 2 and 3 after which it tapered to about 164% of control. The brain level of 3-OMD increased to 870% of the control. SAM was increased by 44% after the sixth day and SAH level was about double after the second day. After day 3, MAT activity was increased by about 35%. Western blot analysis showed that MAT is more clearly characterized in 10% mercaptoethanol reducing buffer in which 31.5-, 38- (beta), and 48-kDa (alpha1/alpha2) subunits were distinctly revealed. The induction of the 38-kDa and, more prominently, the 48-kDa subunits of MAT and the potential transactivator proteins of MAT, c-Jun/AP-1, was evident by day 6. The 31.5-kDa subunit was downregulated. COMT was detected as 24.7-, 30-, and 47.5-kDa bands in the brain, consistent with the membrane-bound COMT I (MB-COMT) and the dimeric COMT II. The 24.7- and the 30-kDa MB-COMT bands were induced in the brain by day 6 and peaked on day 9. The highlight of the study is the fact that L-dopa induces the enzymes MAT and COMT. In addition, the downturn in brain DA after the sixth day coincides with the increase in SAM and the 48-kDa MAT protein. Thus, during PD treatment with L-dopa the induction of MAT and COMT is likely to occur and in turn increase the methylation and reduction of L-dopa and DA that may help cause the tolerance or the wearing-off effect developed to L-dopa.
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PMID:L-dopa upregulates the expression and activities of methionine adenosyl transferase and catechol-O-methyltransferase. 1152 Jan 27

1-Methyl-4-phenyl-pyridinium (MPP(+)) and S-adenosyl-L-methionine (SAM) cause Parkinson's disease (PD)-like changes. SAM and MPP(+) require their charged S-methyl and N-methyl groups, so the PD-like symptoms may be related to their ability to modulate the methylation process. The SAM-dependent methylation of phosphatidylethanolamine (PTE) to produce phosphatidylcholine (PTC), via phosphatidylethanolamine-N-methyltransferase (PEMT), and the hydrolysis of PTC to form lyso-PTC, a cytotoxic agent, are potential loci for the action of MPP(+). In this study, the effects of MPP(+) on the methylation of PTE to PTC and the production of lyso-PTC were determined. The results showed that SAM increased PTC and lyso-PTC. The rat striatum showed the highest PEMT activity and lyso-PTC formation, which substantiate with the fact that the striatum is the major structure that is affected in PD. MPP(+) significantly enhanced PEMT activity and the formation of lyso-PTC in the rat liver and brain. MPP(+) increased the affinity and the V(max) of PEMT for SAM. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) effect was lesser and inhibited by deprenyl (MAO-B inhibitor). The nor-methyl analogs of MPP(+) were inactive, but some of the charged analogs of MPP(+) showed comparable effects to those of MPP(+). Lyso-PTC that can be increased by SAM and MPP(+) caused severe impairments of locomotor activities in rats. These results indicate that SAM and MPP(+) have complementary effects on phospholipid methylation. Thus, SAM-induced hypermethylation could be involved in the etiology of PD and an increase of phospholipid methylation could be one of the mechanisms by which MPP(+) causes parkinsonism.
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PMID:1-Methyl-4-phenyl-pyridinium increases S-adenosyl-L-methionine dependent phospholipid methylation. 1156 47

The convulsant methionine sulfoximine (MSO) is a byproduct of the agenized flour commonly used for feeding domestic animals decades ago. MSO is a powerful glycogenic and epileptogenic agent, and it is an irreversible inhibitor of glutamine synthetase. This latter effect was hypothesized to be responsible for the increase in the incidence of some neuropathologies in humans, such as Alzheimer's disease or Parkinson's disease. In order to test this hypothesis, we chronically administered MSO to two inbred strains of mice, C57BL/6J and BALB/cJ, and analyzed possible alterations in learning and memory features of these mice. Mice were given 20 mg/kg of MSO three times a week for 10 weeks. Spatial learning capabilities assessed with a radial maze were not affected by the long-term MSO treatment, although activity was significantly decreased in BALB/cJ mice. Thus, our data suggest that long-term administration of non-convulsive and non-glycogenic doses of MSO do not alter the spatial memory of mice. Our results do not support the hypothesis that chronic treatment with MSO influences hippocampus-dependent learning abilities in mice.
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PMID:Chronic inhibition of glutamine synthetase is not associated with impairment of learning and memory in mice. 1182 32

One of the hallmarks of Parkinson's disease (PD) is pathological structure, termed Lewy body, containing inclusions of ubiquitinated proteins in the dopaminergic neurons in the substantia nigra. The mechanism leading to the formation of these aggregates is unclear, although it has been shown that mutations in alpha-synuclein or in the ubiquitin-related enzyme UCH-L1 might induce such protein aggregation. We, therefore, examined the possible role of 6-hydroxydopamine (6-OHDA), a dopaminergic neurotoxin used in PD experimental models, in causing protein degradation and its association with the ubiquitin system. Using antiubiquitin antibodies we found that exposure of SH-SY5Y neuroblastoma and PC-12 cell lines to 6-OHDA increased the levels of free ubiquitin and ubiquitin-conjugated proteins, in a dose-dependent manner. Furthermore, metabolic labeling with 35S-methionine, demonstrated that 6-OHDA markedly increased protein degradation, as indicated by the secretion of protein metabolites to the medium. Inhibition of the proteasome activity by the specific inhibitor MG132, attenuated the protein degradation induced by 6-OHDA and potentiated its toxicity. Administration of the antioxidant N-acetylcysteine to the 6-OHDA-treated cells, increased cell survival and reduced protein degradation. In conclusion, our findings suggest that 6-OHDA toxicity is associated with protein degradation and ubiquitin-proteasome system activation.
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PMID:6-Hydroxydopamine increases ubiquitin-conjugates and protein degradation: implications for the pathogenesis of Parkinson's disease. 1204 47

The motor signs of Parkinson's disease have been partly attributed to an overinhibition of the external globus pallidus (GP) that results from hyperactivity of striatopallidal GABA/enkephalinergic neurons. The goals of this study were to measure basal levels of extracellular fluid GABA in the GP of normal cats, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian cats and cats spontaneously recovered from MPTP-induced parkinsonism, and to examine the effects of opioid receptor activation on potassium (K+)-evoked GABA release in the GP in these animals. Basal GP GABA levels were increased 75% from normal in parkinsonian animals 1 week after MPTP administration and returned to control levels in recovered animals 6 weeks after MPTP administration. No significant differences were observed in K+-evoked GABA release across conditions. The opioid receptor agonist [D-Ala2]-Met-Enkephalinamide (DALA) significantly attenuated K+-evoked GABA release in the GP of MPTP-treated symptomatic and recovered cats, but had no significant effect on GABA release in normal animals. These data show that basal GP GABA levels are elevated coincident with expression of parkinsonian signs and return to normal in animals that have functionally compensated for a nigrostriatal lesion. DALA-induced inhibition of pallidal GABA release after a dopamine-depleting lesion, suggests that enkephalin may attenuate GABA release in the GP specifically after striatal dopamine loss.
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PMID:GABA-opioid interactions in the globus pallidus: [D-Ala2]-Met-enkephalinamide attenuates potassium-evoked GABA release after nigrostriatal lesion. 1215 90

Our previous studies showed that S-adenosyl-methionine (SAM) induced Parkinson's disease-like changes in rat. It caused death to dopamine neurons in the substantia nigra, which appeared shrunken and fragmented, indicative of apoptosis-like changes (Charlton and Crowell [1995] Mol. Chem. Neuropathol. 26:269-284; Charlton [1997] Life Sci. 61:495-502). In this study, we investigated whether SAM causes apoptosis in both undifferentiated PC12 (PC12) cells and nerve growth factor (NGF)-differentiated PC12 (D-PC12) cells. S-adenosyl-homocysteine (SAH), the nonmethyl analog of SAM, was also tested. SAM and SAH (1.0 nM to 10.0 microM) caused lactate dehydrogenase (LDH) release from the PC12 cells and D-PC12 cells; cells with morphological changes and fluorescent DNA fragmentation staining were detected among both PC12 cell and D-PC12 cell. Compared with the PC12 cell, the D-PC12 cell, a postmitotic cell, was more sensitive to the toxic effects of SAM or SAH and presented much greater LDH release, suggesting a lethal effect; surprisingly, the amounts of apoptotic cells did not differ significantly between the two kinds of cells. In medium deprived of exogenous methionine, a decline in LDH release was observed in PC12 and D-PC12 cells. Also, lower levels of intracellular SAM and SAH were observed in the methionine-deleted media, which were reversed by the addition of either SAM or SAH. An antivitamin B(12) monoclonal antibody was added to methionine-depleted medium, resulting in deficiency of both endogenous and exogenous methionine, which caused further decreases in LDH release and reduction in the levels of intracellular SAM and SAH. The preliminary data showed different sensitivities to SAM or SAH between PC12 cell and D-PC12 cells, which suggests that PC12 cell may be more stable as a metabolic model. Apoptosis of PC12 cells was also assessed by PARP cleavage detection, Western blot analysis of Bax and Bcl-2 proteins, and DNA laddering on agarose gel electrophoresis. The proapoptoic protein Bax was dominantly expressed, whereas Bcl-2 was slightly down-regulated by SAM. SAH weakly induced the expression of Bax and slightly decreased Bcl-2 levels. The effects of SAM and its analog, SAH, were demonstrated conclusively to induce apoptosis in PC12 cells.
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PMID:S-adenosyl-methionine-induced apoptosis in PC12 cells. 1221 Aug 45

Paraoxonase1 (PON1) is an arylesterase mainly expressed in the liver that hydrolyzes organophosphates such as pesticides, reported risk factors for Parkinson's disease (PD), and other neurotoxins. A Leu-Met 54 polymorphism in the gene for PON1-affecting enzyme activity was recently shown, employing a new restriction enzyme technique, to be associated with Parkinson's disease. We examined the same polymorphism by automated capillary sequencing in a sample of Caucasian subjects from the Stockholm area in Sweden (127 healthy individuals and 114 patients with PD) and found similar distributions and a similar difference in our sample. The genotype distribution in our PD material was LL 36.0%, LM 45.6%, and MM 18.4%; in our control material, it was LL 45.7%, LM 44.1%, and MM 10.2%. Based on the previously established increase in allele frequencies of the lower-activity Met-variant of PON1, we could confirm a significant association using a one-sided chi(2) test. Results remained significant with a two-sided chi(2) test, allowing for both increases and decreases in frequencies. Our data confirm an association between the PON1 Leu-Met 54 polymorphism and PD by demonstrating a similar association. The distribution between familial and nonfamilial PD patients was equal. No other synonymous or nonsynonymous polymorphisms were found in the sequenced coding region of PON1.
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PMID:Further evidence for an association of the paraoxonase 1 (PON1) Met-54 allele with Parkinson's disease. 1221 Aug 72


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