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)

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

There is increasing evidence for a defect of mitochondrial respiratory chain function in Parkinson's disease. Specific NADH CoQ1 reductase (complex I) deficiency has been identified in the substantia nigra. Available evidence suggests that this defect is confined to the substantia nigra and is not present elsewhere in the parkinsonian brain. The absence of a detectable mitochondrial abnormality in the substantia nigra of patients with multiple system atrophy also suggests that the complex I deficiency in Parkinson's disease is not simply due to an artifact of neuronal degeneration. Evidence for abnormal mitochondrial function in skeletal muscle is conflicting; two studies showed multiple respiratory chain defects and one study was unable to demonstrate any deficiency. A severe deficiency of complex I activity has been found in platelet mitochondria from parkinsonian patients. This finding has not as yet been confirmed. Platelet homogenates do not show the complex I deficiency, however, suggesting that such a preparation may be too insensitive to detect the defect. The role of complex I deficiency in the events that culminate in dopaminergic cell death in Parkinson's disease remains unresolved. It is likely that if this mitochondrial defect is confirmed, it will be related to a number of other factors, including environmental agents, oxidative stress, and genetic predisposition.
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PMID:Mitochondrial function in Parkinson's disease. The Royal Kings and Queens Parkinson's Disease Research Group. 151 Mar 69

We measured metabolites of tyrosine and tryptophan (TRP) in the frontal cortex, putamen (PT), and pars compacta of the substantia nigra (SN) of control and Parkinson's disease (PD) brain tissues. Dopamine concentrations were significantly decreased in the PT and SN of PD tissue, regardless of L-dopa therapy. However, 3-O-methyldopa (3OMD) concentration showed a significant increase in each region of the PD group treated with L-dopa (PD[+]) as compared with both the control group and the PD group without L-dopa therapy (PD[-]). Therefore, 3OMD concentration appears to be a reliable marker of L-dopa therapy. Serotonin concentration was lower in each region of the PD groups than in the control group. Although the magnitude of decrease was greater in the PD(+) group, there was no statistical significance between the two PD groups. The same patterns of decrease were present in kynurenine (KYN) and kynurenic acid (KYA) concentrations, but the molar ratios of TRP to KYN and KYN to KYA were unchanged among three groups. In contrast, 3-hydroxykynurenine (3OHKY) concentration was increased in the PT PD(-) group and in three regions of the PD(+) group. Since the KYN pathway leads to formation of nicotinamide-adenine dinucleotide (NADH), the present results may be a further indication of a defect in NADH:ubiquinone oxidoreductase (complex I) in mitochondria in PD.
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PMID:Kynurenine pathway abnormalities in Parkinson's disease. 151 57

Parkinson's disease is one of the commonest neurodegenerative disorders in Western society. Although the neuropathological changes have been well documented, the underlying biochemical defect is unknown. Toxins may play a part in the aetiology of this disorder. It has been shown that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a Parkinson-like syndrome in both man and primates and 1-methyl-4-phenylpyridine (MPP+), a metabolite of MPTP, inhibits NADH-ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain. We studied mitochondrial respiratory chain function in skeletal muscle from patients with Parkinson's disease because, like brain, it has a high dependence on oxidative metabolism. Our results show low activity in all complexes studied (I, II and IV). The implications of these findings are discussed in relation to the aetiology of Parkinson's disease.
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PMID:Respiratory chain abnormalities in skeletal muscle from patients with Parkinson's disease. 165 41

Dysfunction of NADH: ubiquinone oxidoreductase (complex I) of the mitochondrial electron transport chain has been linked to the pathogenesis of Parkinson's disease. While simple assays of complex I activity are unlikely to be useful in the preclinical detection of Parkinson's disease, other more sophisticated physical-chemical approaches including detection of free radical damage may have utility. Leber's hereditary optic neuropathy may provide a useful model system for development of such strategies.
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PMID:Preclinical detection of Parkinson's disease: biochemical approaches. 190 40

The reduced form of nicotinamide adenine dinucleotide coenzyme Q reductase (complex I) activity has recently been shown to be deficient in the substantia nigra of patients dying with Parkinson's disease. This biochemical defect is identical to that produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which also produces parkinsonism in humans. Complex I comprises 25 polypeptides, seven of which are encoded by mitochondrial DNA. Restriction fragment analysis of substantia nigra DNA from six patients with Parkinson's disease did not show any major deletion. In two cases, there were different novel polymorphisms that were not observed in control brain (n = 6) or blood (n = 34) samples.
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PMID:Mitochondrial DNA analysis in Parkinson's disease. 197 56

Effects of MPTP-like compounds on mitochondrial respiration, activity of NADH-ubiquinone oxidoreductase (complex I) and on ATP synthesis were reported. Mitochondria prepared from mouse whole brains were used. The compounds tested include tetrahydroisoquinoline (TIQ), tetrahydropapaveroline (THP), tetrahydropapaverine (THPV), and salsolinol. TIQ, THP, and THPV significantly inhibited the state 3 respiration supported by glutamate + malate, activity of complex I and ATP synthesis. Among these compounds, THPV was most potent. Toxic properties of these compounds on mitochondria were similar to MPP+. Significance of our results was discussed with respect to etiology of Parkinson's disease.
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PMID:Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-like compounds on mitochondrial respiration. 212 45

Effects of tetrahydroisoquinoline (TIQ) on mitochondrial respiration, NADH-ubiquinone oxidoreductase (complex I) activity and on adenosine triphosphate (ATP) synthesis were studied using mitochondria prepared from mouse brains. Tetrahydroisoquinoline significantly inhibited mitochondrial respiration supported by glutamate + malate, pyruvate + malate or alpha-ketoglutarate. Activity of complex I and synthesis of ATP were also significantly inhibited by TIQ. Mitochondrial respiration supported by succinate and subsequent ATP synthesis were not inhibited at all by 5 mM of TIQ. Our study has revealed a novel action of TIQ, which has been proposed as a candidate for an endogenous substance that may induce Parkinson's disease.
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PMID:Inhibition of mitochondrial NADH-ubiquinone oxidoreductase activity and ATP synthesis by tetrahydroisoquinoline. 312 81

Neuroleptic medications are prescribed to millions of patients, but their use is limited by potentially irreversible extrapyramidal side effects. Haloperidol shows striking structural similarities to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which produces parkinsonism apparently through inhibition of NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial electron transport chain. We now report that haloperidol, chlorpromazine, and thiothixene inhibit complex I in vitro in rat brain mitochondria. Clozapine, an atypical antipsychotic reported to have little or no extrapyramidal toxicity, also inhibits complex I, but at a significantly higher concentration. Neuroleptic treated patients have significant depression of platelet complex I activity similar to that seen in idiopathic Parkinson's disease. Complex I inhibition may be associated with the extrapyramidal side effects of these drugs.
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PMID:Neuroleptic medications inhibit complex I of the electron transport chain. 790 2

Defects of the human mitochondrial respiratory chain have been associated with several diseases including, most recently, certain neurodegenerative disorders. Several studies have used platelet mitochondrial function as a means to determine the potential contribution of respiratory chain defects to the pathogenesis of Parkinson's disease. Platelet biochemistry is subject to modulation by numerous factors that may circulate in the blood, including environmental agents, some of which may be relevant to mitochondrial dysfunction and neuronal toxicity. We measured mitochondrial respiratory chain enzyme activities in platelets from 18 normal healthy non-smoking controls and compared them with those from 23 similarly healthy cigarette smoking individuals. A 24% decrease (p < 0.02) was observed in the mean NADH CoQ1 reductase (complex I) activity of the smoking group compared with that of the non-smoking group. There was no significant change in the activity of any of the other respiratory chain enzymes. This is the first demonstration in vivo of mitochondrial inhibition by a common environmental agent. The results offer a novel mechanism of action for the cellular toxicity, or even mutagenicity, associated with cigarette smoking. In addition, these data have important implications for the interpretation of platelet mitochondrial complex I activities in disease states. They are particularly relevant to our interpretation and understanding of the complex I deficiency in Parkinson's disease platelets.
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PMID:Smoking and mitochondrial function: a model for environmental toxins. 825 63


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