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)

There is increasing evidence that defective function of the mitochondrial enzyme NADH CoQ reductase (complex I) is involved not only in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, but also in idiopathic Parkinson's disease (PD). Complex I deficiency has been identified in PD substantia nigra and appears to be disease-specific and selective for the substantia nigra within the central nervous system. We describe a method for preparation of an enriched mitochondrial fraction from 60 mL blood. Using this technique, we analyzed respiratory chain function in 25 patients with PD and 15 matched control subjects. We confirm a previous report of a specific complex I deficiency in PD platelet mitochondria. Although there was a statistically significant decrease in complex I activity in the PD group compared with the control group (p = 0.005), the defect was mild (16%); it was not possible to distinguish PD from control values on an individual basis. This deficiency is not detectable in platelet whole-cell homogenates, presumably reflecting the relative insensitivity of this preparation and the limited decrease in complex I activity in PD. The presence of a mild complex I defect in platelets together with a more severe defect in substantia nigra suggests either that the pharmacological characteristics shared by these two tissues render them susceptible to a particular toxin or toxins, or that the defect is widely distributed and other biochemical events enhance the deficiency in substantia nigra.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet mitochondrial function in Parkinson's disease. The Royal Kings and Queens Parkinson Disease Research Group. 147 69

The evidence is compelling that free radicals, plus increases in free cytosolic Ca2+ and Na+, figure prominently in neuronal death after exposure to glutamate and dicarboxylic excitotoxins such as NMDA and kainate. However, neither the source of these radicals nor the direct connection between Ca2+ mobilization and radical production has been well defined. Electron paramagnetic resonance studies reported here indicate that intact mitochondria isolated from adult rat cerebral cortex and cerebellum generate extremely reactive hydroxyl (.OH) radicals, plus ascorbyl and other carbon-centered radicals when exposed to 2.5 microM Ca2+, 14 mM Na+, plus elevated ADP under normoxic conditions, circumstances that prevail in the cytoplasm of neurons during excitotoxin-induced neurodegeneration. In a feed-forward cycle, exposure of isolated mitochondria to .OH significantly increases subsequent radical production five- to 16-fold (average = 8.8 +/- 1.6 SE, n = 6, p > 0.01) with succinate as substrate, and also selectively impairs function of NADH-CoQ dehydrogenase activity (electron transport complex 1). These effects are also reflected by respiration rates that are reduced 48% with complex 1 substrates, but increased 27% with complex 2 substrate, after .OH exposure. Comparable complex 1 dysfunction is observed in mitochondria isolated from the substantia nigra of Parkinson's disease patients, from platelets of Huntington's disease patients, and from neocortex of Alzheimer's disease patients. Mitochondrial radical production provides a testable model, based on oxyradical toxicity, oxidative enzyme inactivation, and mitochondrial dysfunction, for the final common pathway of neuronal necrosis during excitotoxicity, and in a host of neurodegenerative disorders.
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PMID:Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated CA2+ and Na+: implications for neurodegeneration. 803 83

The major initial product of the oxidation of norepinephrine (NE) in the presence of L-cysteine is 5-S-cysteinylnorepinephrine which is then further easily oxidized to the dihydrobenzothiazine (DHBT) 7-(1-hydroxy-2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1, 4-benzothiazine-3-carboxylic acid (DHBT-NE-1). When incubated with intact rat brain mitochondria, DHBT-NE-1 evokes rapid inhibition of complex I respiration without affecting complex II respiration. DHBT-NE-1 also evokes time- and concentration-dependent irreversible inhibition of NADH-coenzyme Q(1) (CoQ(1)) reductase, the pyruvate dehydrogenase complex (PDHC), and alpha-ketoglutarate dehydrogenase (alpha-KGDH) when incubated with frozen and thawed rat brain mitochondria (mitochondrial membranes). The time dependence of the inhibition of NADH-CoQ(1) reductase, PDHC, and alpha-KGDH by DHBT-NE-1 appears to be related to its oxidation, catalyzed by an unknown component of the inner mitochondrial membrane, to electrophilic intermediates which bind covalently to active site cysteinyl residues of these enzyme complexes. The latter conclusion is based on the ability of glutathione to block inhibition of NADH-CoQ(1) reductase, PDHC, and alpha-KGDH by scavenging electrophilic intermediates, generated by the mitochondrial membrane-catalyzed oxidation of DHBT-NE-1, forming glutathionyl conjugates, several of which have been isolated and spectroscopically identified. The possible implications of these results to the degeneration of neuromelanin-pigmented noradrenergic neurons in the locus ceruleus in Parkinson's disease are discussed.
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PMID:Oxidative metabolites of 5-S-cysteinylnorepinephrine are irreversible inhibitors of mitochondrial complex I and the alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase complexes: possible implications for neurodegenerative brain disorders. 1095 63

Two substances which are products of the isoprenoid pathway, can participate in lipid peroxidation. One is digoxin, which by inhibiting membrane Na(+)-K+ ATPase, causes increase in intracellular Ca2+ and depletion of intracellular Mg2+, both effects contributing to increase in lipid peroxidation. Ubiquinone, another products of the pathway is a powerful membrane antioxidant and its deficiency can also result in defective electron transport and generation of reactive oxygen species. In view of this and also in the light of some preliminary reports on alteration in lipid peroxidation in neuropsychiatric disorders, a study was undertaken on the following aspects in some of these disorders (primary generalised epilepsy, schizophrenia, multiple sclerosis, Parkinson's disease and CNS glioma)--1) concentration of digoxin, ubiquinone, activity of HMG CoA reductase and RBC membrane Na(+)-K+ ATPase 2) activity of enzymes involved in free radical scavenging 3) parameters of lipid peroxidation and 4) antioxidant status. The result obtained indicates an increase in the concentration of digoxin and activity of HMG CoA reductase, decrease in ubiquinone levels and in the activity of membrane Na(+)-K+ ATPase. There is increased lipid peroxidation as evidenced from the increase in the concentration of MDA, conjugated dienes, hydroperoxides and NO with decreased antioxidant protection as indicated by decrease in ubiquinone, vit E and reduced glutathione in schizophrenia, Parkinson's disease and CNS glioma. The activity of enzymes involved in free radical scavenging like SOD, catalase, glutathione peroxidase and glutathione reductase is decreased in the above diseases. However, there is no evidence of any increase in lipid peroxidation in epilepsy or MS. The role of increased operation of the isoprenoid pathway as evidenced by alteration in the concentration of digoxin and ubiquinone in the generation of free radicals and protection against them in these disorders is discussed.
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PMID:Isoprenoid pathway and free radical generation and damage in neuropsychiatric disorders. 1127 6

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease affecting approximately1% of the population older than 50 years. There is a worldwide increase in disease prevalence due to the increasing age of human populations. A definitive neuropathological diagnosis of Parkinson's disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha-synuclein gene on chromosome 4 in the much more common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson's disease. Oxidative phosphorylation consists of five protein-lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II (succinate:ubiquinone oxidoreductase, EC 1.3.5.1), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1), and complex V (ATP synthase, EC 3.6.1.34). A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons.
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PMID:Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of parkinson's disease. 1135 Nov 30

Features of Parkinson's disease (PD) include oxidative stress, nigral mitochondrial complex I deficiency and visual dysfunction, all of which are also associated with coenzyme Q(10) (CoQ(10)) deficiency. The objective of this monocenter, parallel group, placebo controlled, double-blind trial was to determine the symptomatic response of daily oral application of 360 mg CoQ(10) lasting 4 weeks on scored PD symptoms and visual function, measured with the Farnsworth-Munsell 100 Hue test (FMT), in 28 treated and stable PD patients. CoQ(10) supplementation provided a significant (P=0.01) mild symptomatic benefit on PD symptoms and a significantly (F((1,24))=8.48, P=0.008) better improvement of FMT performance compared with placebo. Our results indicate a moderate beneficial effect of oral CoQ(10) supplementation in PD patients.
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PMID:Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson's disease. 1269 83

The simplest explanation for the selective loss of substantia nigra (SN) dopamine (DA) neurons in Parkinson's disease (PD) is that DA or a metabolite is neurotoxic. Recently, a series of investigations implicate the MAO metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as the critical endogenous toxin which triggers DA neuron loss in PD: 1. Hereditary PD contains mutations in the gene for alpha-synuclein (alpha-syn). Investigations implicate a DA metabolite as mediator of alpha-syn neurotoxicity, and DOPAL is 1000-fold more toxic than DA in vivo. 2. A deficit in mitochondrial complex I is found in PD SN. Inhibition of complex I causes increases in DOPAL levels and death of DA neurons in vitro and in vivo. 3. L-DOPA, the precursor of DA, which is used to treat PD, is toxic and contributes to the progression of PD. L-DOPA-treated rats have an 18-fold increase in striatal DOPAL. 4. Free hydroxyl radicals (.OH) trigger aggregation of alpha-syn to its toxic form. DOPAL with H(2)O(2) generates.OH radicals. These investigations provide several therapeutic strategies to limit DOPAL toxicity and progression of PD: 1. Delaying the start of L-DOPA therapy by early use of DA receptor agonists, which may also be free radical scavengers, limits the amount of DOPAL formed from L-DOPA. 2. Nonspecific MAO inhibitors may more effectively decrease production of DOPAL from DA than MAO-B inhibitors. 3. Newer more potent and targeted free radical scavengers could block DOPAL toxicity. 4. Coenzyme Q(10) increases complex I activity and nicotine adenine dinucleotide (NAD) synthesis, and thereby could enhance DOPAL catabolism by aldehyde dehydrogenase, which uses NAD as a cofactor. 5. DA uptake blockers could be used to limit intraneuronal DOPAL production. 6. Tauroursodeoxycholic acid, an inhibitor of apoptosis shown to be effective in models of Huntington's disease, may also prove effective in blocking DOPAL toxicity in PD. 7. Agents which block aggregation of alpha-syn should limit DOPAL toxicity.
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PMID:3,4-dihydroxyphenylacetaldehyde: a potential target for neuroprotective therapy in Parkinson's disease. 1276 6

Parkinson's disease is characterized by dopamine cell loss of the substantia nigra. Parkinson's disease and the neurotoxin 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine may destroy dopamine neurons through oxidative stress. Coenzyme Q is a cofactor of mitochondrial uncoupling proteins that enhances state-4 respiration and eliminate superoxides. Here we report that short-term oral administration of coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine administration in monkeys.
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PMID:Coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss in a primate model of Parkinson's disease. 1281 May 26

Coenzyme Q(10) (ubiquinone), which serves as the electron acceptor for complexes I and II of the mitochondrial electron transport chain and also acts as an antioxidant, has the potential to be a beneficial agent in neurodegenerative diseases in which there is impaired mitochondrial function and/or excessive oxidative damage. Substantial data have accumulated to implicate these processes in the pathogenesis in certain neurodegenerative disorders, including Parkinson's disease, Huntington's disease and Friedreich's ataxia. Although no study to date has unequivocally demonstrated that coenzyme Q(10) can slow the progression of a neurodegenerative disease, recent clinical trials in these three disorders suggest that supplemental coenzyme Q(10) can slow the functional decline in these disorders, particularly Parkinson's disease.
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PMID:Coenzyme Q10 in neurodegenerative diseases. 1287 Oct 93

Dopamine, which is suggested as a prominent etiological factor in several neuropsychiatric disorders such as Parkinson's disease and schizophrenia, demonstrates neurotoxic properties. In such dopamine-related diseases mitochondrial dysfunction has been reported. Dopamine oxidized metabolites were shown to inhibit the mitochondrial respiratory system both in vivo and in vitro. In the present study, we suggest an additional mechanism for dopamine toxicity, which involves mitochondrial complex I inhibition by dopamine. In human neuroblastoma SH-SY5Y cells dopamine induced a reduction in ATP concentrations, which was negatively correlated to intracellular dopamine levels (r = - 0.96, P = 0.012), and was already evident at non-toxic dopamine doses. In disrupted mitochondria dopamine inhibited complex I activity with IC50 = 11.87 +/- 1.45 microm or 8.12 +/- 0.75 microM in the presence of CoQ or ferricyanide, respectively, with no effect on complexes IV and V activities. The catechol moiety, but not the amine group, of dopamine is essential for complex I inhibition, as is indicated by comparing the inhibitory potential of functionally and structurally dopamine-related compounds. In line with the latter is the finding that chelatable FeCl2 prevented dopamine-induced inhibition of complex I. Monoamine oxidase A and B inhibitors, as well as the antioxidant butylated hydroxytoluene (BHT), did not prevent dopamine-induced inhibition, suggesting that dopamine oxidation was not involved in this process. The present study suggests that dopamine toxicity involves, or is initiated by, its interaction with the mitochondrial oxidative phosphorylation system. We further hypothesize that this interaction between dopamine and mitochondria is associated with mitochondrial dysfunction observed in dopamine-related neuropsychiatric disorders, such as schizophrenia and Parkinson's disease.
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PMID:Dopamine toxicity involves mitochondrial complex I inhibition: implications to dopamine-related neuropsychiatric disorders. 1513 Jul 72


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