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 aggregation of normally soluble alpha-synuclein in the dopaminergic neurons of the substantia nigra is a crucial step in the pathogenesis of Parkinson's disease. Oxidative stress is believed to be a contributing factor in this disorder. Because it lacks Trp and Cys residues, mild oxidation of alpha-synuclein in vitro with hydrogen peroxide selectively converts all four methionine residues to the corresponding sulfoxides. Both oxidized and non-oxidized alpha-synucleins have similar unfolded conformations; however, the fibrillation of alpha-synuclein at physiological pH is completely inhibited by methionine oxidation. The inhibition results from stabilization of soluble oligomers of Met-oxidized alpha-synuclein. Furthermore, the Met-oxidized protein also inhibits fibrillation of unmodified alpha-synuclein. The degree of inhibition of fibrillation by Met-oxidized alpha-synuclein is proportional to the number of oxidized methionines. However, the presence of metals can completely overcome the inhibition of fibrillation of the Met-oxidized alpha-synuclein. Since oligomers of aggregated alpha-synuclein may be cytotoxic, these findings indicate that both oxidative stress and environmental metal pollution could play an important role in the aggregation of alpha-synuclein, and hence possibly Parkinson's disease. In addition, if the level of Met-oxidized alpha-synuclein was under the control of methionine sulfoxide reductase (Msr), then this could also be factor in the disease.
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PMID:Methionine oxidation, alpha-synuclein and Parkinson's disease. 1568 Feb 24

Previous studies demonstrated that alpha-synuclein (alpha-syn) fibrillization is inhibited by dopamine, and studies to understand the molecular basis of this process were conducted (Conway, K. A., Rochet, J. C., Bieganski, R. M., and Lansbury, P. T., Jr. (2001) Science 294, 1346-1349). Dopamine inhibition of alpha-syn fibrillization generated exclusively spherical oligomers that depended on dopamine autoxidation but not alpha-syn oxidation, because mutagenesis of Met, His, and Tyr residues in alpha-syn did not abrogate this inhibition. However, truncation of alpha-syn at residue 125 restored the ability of alpha-syn to fibrillize in the presence of dopamine. Mutagenesis and competition studies with specific synthetic peptides identified alpha-syn residues 125-129 (i.e. YEMPS) as an important region in the dopamine-induced inhibition of alpha-syn fibrillization. Significantly, the dopamine oxidation product dopaminochrome was identified as a specific inhibitor of alpha-syn fibrillization. Dopaminochrome promotes the formation of spherical oligomers by inducing conformational changes, as these oligomers regained the ability to fibrillize by simple denaturation/renaturation. Taken together, these data indicate that dopamine inhibits alpha-syn fibrillization by inducing structural changes in alpha-syn that can occur through the interaction of dopaminochrome with the 125YEMPS129 motif of alpha-syn. These results suggest that the dopamine autoxidation can prevent alpha-syn fibrillization in dopaminergic neurons through a novel mechanism. Thus, decreased dopamine levels in substantia nigra neurons might promote alpha-syn aggregation in Parkinson's disease.
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PMID:Reversible inhibition of alpha-synuclein fibrillization by dopaminochrome-mediated conformational alterations. 1581 78

Idiopathic Parkinson's disease (IPD) is a neurodegenerative disorder of unknown aetiology. Histopathological similarities between IPD and Creutzfeldt-Jakob prion disease (CJD) have been suggested. Homozygosity at polymorphic prion protein gene codon 129 (PRNP129) is a risk factor for developing CJD. Therefore we investigated a putative genetic link between CJD and IPD by studying PRNP129 genotype segregation in 81 patients with IPD. We did not ascertain a different PRNP129 genotype distribution in IPD patients compared to healthy Germans. We found a significant difference in PRNP129 genotype in dependence of the clinical predominance type of IPD. Patients with tremor-dominant IPD presented less frequent a methionine homozygosis at PRNP129 than hypokinetic-rigid IPD patients (30% versus 62.5%; p<0.033). In conclusion, genotype distribution at codon 129 is obviously not essential in determining IPD. But our results may provide first evidence of an association between certain PRNP129 polymorphisms and the clinical presentation of IPD.
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PMID:Analysis of the polymorphic prion protein gene codon 129 in idiopathic Parkinson's disease. 1599 18

Homocysteine (Hcy) is a thyol amino acid resulting from de-methylation of methionine, an essential amino acid derived from dietary proteins. It is metabolized through two pathways: re-methylation and transsulfuration, which use as cofactors folate, vitamin B6 and vitamin B12. Hyperhomocysteinemia has been identified as a risk factor for cerebrovascular disease, dementia, impaired cognitive function and depression. Several drugs may interfere with metabolic pathways of Hcy, leading to an alteration of plasma Hcy levels. Lipid-lowering agents, used to reduce the risk of cerebral venous thrombosis or occlusive vascular disease in patients with high levels of plasmatic lipids, can increase plasma Hcy levels. Hyperhomocysteinemia has been also documented in Parkinson disease patients treated with levodopa and in epileptic patients after chronic treatment with antiepileptic drugs. In contrast, vitamins supplementations may be warranted in patients treated with lipid-lowering agents, levodopa and antiepileptic drugs in order to maintain normal plasma Hcy values. In contrast, higher doses of vitamins can induce dysfunctions in central and peripheral nervous system; therefore excessive supplements should be avoided.
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PMID:Increase in plasma homocysteine levels induced by drug treatments in neurologic patients. 1603 38

Metabolism of levodopa via the enzyme catechol-O-methyltransferase requires S-adenosylmethionine (SAM) as a methyl donor. SAM caused Parkinson disease (PD)-like symptoms in rodents. Therefore, SAM could contribute to a decreased efficacy of levodopa in the long term. SAM levels were significantly reduced in levodopa-treated PD patients, but they showed increased enzyme methionine adenosyl transferase (MAT) activity, which induces SAM synthesis from methionine (MET). This may result from a rebound increase of SAM production. The objective of the study was to demonstrate an effect of acute levodopa intake on SAM synthesis in the plasma of treated PD patients. The authors measured SAM, MET, and levodopa plasma concentrations in 13 levodopa-treated PD patients before and after application of 125 mg levodopa/benserazide. Plasma levels of SAM and levodopa significantly increased, but MET concentrations did not significantly decrease. The SAM increase after levodopa intake may exert both a certain antidepressant and cognitive function improving effect. This is often observed in untreated PD patients who receive levodopa for the first time, or in more advanced, fluctuating PD patients, when they turn from the OFF to the ON phase. Because SAM in higher dosages may also counteract the antiparkinsonian efficacy of levodopa according to animal trials, this SAM increase may hypothetically contribute to the onset of wearing-off phenomena and other clinical signs of limited efficacy of levodopa during long-term treatment with levodopa in PD patients.
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PMID:Levodopa intake increases plasma levels of S-adenosylmethionine in treated patients with Parkinson disease. 1634 Mar 82

Mutations in DJ-1 cause an autosomal recessive, early onset familial form of Parkinson disease (PD). However, little is presently known about the role of DJ-1 in the more common sporadic form of PD and in other age-related neurodegenerative diseases, such as Alzheimer disease (AD). Here we report that DJ-1 is oxidatively damaged in the brains of patients with idiopathic PD and AD. By using a combination of two-dimensional gel electrophoresis and mass spectrometry, we have identified 10 different DJ-1 isoforms, of which the acidic isoforms (pI 5.5 and 5.7) of DJ-1 monomer and the basic isoforms (pI 8.0 and 8.4) of SDS-resistant DJ-1 dimer are selectively accumulated in PD and AD frontal cortex tissues compared with age-matched controls. Quantitative Western blot analysis shows that the total level of DJ-1 protein is significantly increased in PD and AD brains. Mass spectrometry analyses reveal that DJ-1 is not only susceptible to cysteine oxidation but also to previously unsuspected methionine oxidation. Furthermore, we show that DJ-1 protein is irreversibly oxidized by carbonylation as well as by methionine oxidation to methionine sulfone in PD and AD. Our study provides new insights into the oxidative modifications of DJ-1 and indicates association of oxidative damage to DJ-1 with sporadic PD and AD.
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PMID:Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases. 1651 9

Choline is an essential nutrient for all cells because it plays a role in the synthesis of the membrane phospholipid components of the cell membranes, as a methyl-group donor in methionine metabolism as well as in the synthesis of the neurotransmitter acetylcholine. Choline deficiency affects the expression of genes involved in cell proliferation, differentiation, and apoptosis, and it has been associated with liver dysfunction and cancer. Abnormal choline transport and metabolism have been implicated in a number of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Therefore, the study of choline transport and the characteristics of choline transporters are of central importance to understanding the mechanisms that underlie membrane integrity and cell signaling in such disorders. Kinetic studies with radiolabeled choline and inhibitors distinguish three systems for choline transport: (i) low-affinity facilitated diffusion, (ii) high-affinity, Na+-dependent transport, and (iii) intermediate-affinity, Na+-independent transport. It is only recently, however, that the proteins having transport characteristics of at least one of these systems have been identified. They include (i) polyspecific organic cation transporters (OCTs) with low affinity for choline, (ii) high-affinity choline transporters (CHT1s), and (iii) intermediate-affinity choline transporter-like (CTL1) proteins. CHT1 and CTL1 but not OCT transporters are selectively inhibited with hemicholinium-3 and essentially display characteristics of specialized transporters for targeted choline metabolism. CHT1 is abundant in neurons and almost exclusively supplies choline for acetyl-choline synthesis. The focus here is more on newly-discovered CTL1 choline transporters. They are expressed in different organisms and cell types, apparently not for the biosynthesis of acetylcholine but for the production of the most abundant metabolite of choline, the membrane lipid phosphatidylcholine.
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PMID:Choline transport for phospholipid synthesis. 1663 97

No direct data exist on the influence of supranormal intakes of sulfur amino acids on immune function in humans. However 3 major products of sulfur amino acids, glutathione (GSH), homocysteine (Hcy), and taurine (Tau), influence, mainly, inflammatory aspects of the immune response in vitro and in vivo. Methionine intakes above approximately 1 g/d transiently raise plasma Tau, Hcy, and GSH. Tau and GSH ameliorate inflammation. Hcy has the opposite effect. A biphasic relation, between cellular GSH and CD4+ and CD8+ numbers occurs in healthy men. How changes in sulfur amino acid intake influence this phenomenon is unknown. In animals, high Tau intakes are antiinflammatory. How immune function in humans is affected is unknown. A positive relation between plasma neopterin (a marker of a Th-1-type immune response) and Hcy indicates that Hcy may play a part in inflammatory aspects of Parkinson's disease and aging. In vitro, Hcy, at concentrations seen following consumption of approximately 6 g L-methionine/d in adults, increases the interactions among T lymphocytes, monocytes, and endothelium. Whether a similar phenomenon occurs in vivo is unknown. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with raised plasma Hcy in young but not old subjects. The relation of this observation to immune function is unknown. The relationships among Hcy, inflammatory aspects of disease, and in vitro alterations in immune cell behavior create a cautionary note about supplementation of diets with l-methionine to raise intake above approximately 1 g/d. Studies directly linking methionine intake, genetics, plasma Hcy, Tau, and GSH and immune function are needed.
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PMID:The effects of sulfur amino acid intake on immune function in humans. 1670 36

Alpha-synuclein, a presynaptic protein associated with Parkinson's disease, is found as both soluble cytosolic and membrane-bound forms. Although the function of alpha-synuclein is unknown, several observations suggest that its association with membranes is important. In the present study we investigated the effect of alpha-synuclein on lipid oxidation in membranes containing phospholipids with unsaturated fatty acids. The kinetics of lipid oxidation were monitored by the change in fluorescence intensity of the dye C11-BODIPY. We find that monomeric alpha-synuclein efficiently prevented lipid oxidation, whereas fibrillar alpha-synuclein had no such effect. Our data suggest that the prevention of unsaturated lipid oxidation by alpha-synuclein requires that it bind to the lipid membrane. The antioxidant function of alpha-synuclein is attributed to its facile oxidation via the formation of methionine sulfoxide, as shown by mass spectrometry. These findings suggest that the inhibition of lipid oxidation by alpha-synuclein may be a physiological function of the protein.
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PMID:Alpha-synuclein can function as an antioxidant preventing oxidation of unsaturated lipid in vesicles. 1680 Jun 38

Oxidative stress and diminished glutathione pools play critical roles in the pathogenesis of neurodegenerative diseases, including Alzheimer and Parkinson disease. Synthesis of glutathione, the most abundant mammalian antioxidant, is regulated at the substrate level by cysteine, which is synthesized from homocysteine via the transsulfuration pathway. Elevated homocysteine and diminished glutathione levels, seen in Alzheimer and Parkinson disease patients suggest impairments in the transsulfuration pathway that connects these metabolites. However, the very existence of this metabolic pathway in the brain is a subject of controversy. The product of the first of two enzymes in this pathway, cystathionine, is present at higher levels in brain as compared with other organs. This, together with the reported absence of the second enzyme, gamma-cystathionase, has led to the suggestion that the transsulfuration pathway is incomplete in the brain. In this study, we incubated mouse and human neurons and astrocytes and murine brain slices in medium with [35S]methionine and detected radiolabel incorporation into glutathione. This label transfer was sensitive to inhibition of gamma-cystathionase. In adult brain slices, approximately 40% of the glutathione was depleted within 10 h following gamma-cystathionase inhibition. In cultured human astrocytes, flux through the transsulfuration pathway increased under oxidative stress conditions, and blockade of this pathway led to reduced cell viability under oxidizing conditions. This study establishes the presence of an intact transsulfuration pathway and demonstrates its contribution to glutathione-dependent redox-buffering capacity under ex vivo conditions in brain cells and slices.
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PMID:A functional transsulfuration pathway in the brain links to glutathione homeostasis. 1700 61


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