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)

Idiopathic Parkinson's disease may have a low-level familial association but does not follow mendelian patterns of inheritance. Since inheritance of some components of the electron transport chain is nonmendelian and since inhibition of the electron transport chain with the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine models Parkinson's disease in humans and animals, we evaluated catalytic activities of the electron transport chain in platelet mitochondria purified from patients with idiopathic Parkinson's disease. All 10 patients studied had significant reductions of complex I (NADH:ubiquinone oxidoreductase) activity. Succinate:cytochrome c oxidoreductase activity was less strikingly reduced. We hypothesize that the complex I abnormality may have an etiological role in the pathogenesis of Parkinson's disease and that this defect may be derived via the mitochondrial genome.
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PMID:Abnormalities of the electron transport chain in idiopathic Parkinson's disease. 255 92

Inhibition of mitochondrial energy production by MPP+ may be the key step in chemically-induced Parkinson's disease. Tetraphenylboron (TPB-) markedly enhances the effect of MPP+. Inhibition of respiration and uptake of MPP+ are accelerated, the former by up to two orders of magnitude. TPB increases the final concentration of MPP+ in the matrix by 2-3 fold, insufficient to explain the rapid inhibition of respiration. TPB- lowers the membrane surface potential by only about 20%, but increases the partitioning of MPP+ into organic solvent by one order of magnitude. TPB- also enhances the effect of MPP+ on inverted membranes, reducing the I50 by an order of magnitude. We suggest that TPB- acts by ion pairing with MPP+ to facilitate penetration into mitochondria as well as access to a hydrophobic inhibition site on NADH dehydrogenase.
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PMID:Enhancement by tetraphenylboron of the interaction of the 1-methyl-4-phenylpyridinium ion (MPP+) with mitochondria. 278 81

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

Aging is a major risk factor for several common neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Huntington's disease (HD). Recent studies have implicated mitochondrial dysfunction and oxidative stress in the aging process and also in the pathogenesis of neurodegenerative diseases. In brain and other tissues, aging is associated with progressive impairment of mitochondrial function and increased oxidative damage. In PD, several studies have demonstrated decreased complex I activity, increased oxidative damage, and altered activities of antioxidant defense systems. Some cases of familial ALS are associated with mutations in the gene for Cu, Zn superoxide dismutase (Cu, Zn SOD) and decreased Cu, Zn SOD activity, while in sporadic ALS oxidative damage may be increased. Defects in energy metabolism and increased cortical lactate levels have been detected in HD patients. Studies of AD patients have identified decreased complex IV activity, and some patients with AD and PD have mitochondrial DNA mutations. The age-related onset and progressive course of these neurodegenerative diseases may be due to a cycling process between impaired energy metabolism and oxidative stress.
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PMID:Bioenergetic and oxidative stress in neurodegenerative diseases. 747 93

Blue native polyacrylamide gel electrophoresis (BN-PAGE), a method for the isolation of native membrane proteins from biological membranes, was adapted to the isolation of oxidative phosphorylation (OXPHOS) enzymes from milligram amounts of human tissues. Combined with Tricine-sodium dodecyl sulfate (SDS)-PAGE in the second dimension, the protein subunits of OXPHOS complexes could be analyzed and quantified. The characteristics of the technique are described and protocols for processing different tissues are provided. The technique was applied for the analysis of defects of OXPHOS complexes in Parkinson's disease. A significant reduction of complex V was observed in one case. Absolutely normal complex I protein amounts were in contrast to reduced catalytic activities of complex I in Parkinson's disease. This discrepancy can be explained by binding of endogenous complex I inhibitors or by alterations of a protein subunit not affecting the assemblage of the complex but modifying the enzymatic properties.
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PMID:Quantification of oxidative phosphorylation enzymes after blue native electrophoresis and two-dimensional resolution: normal complex I protein amounts in Parkinson's disease conflict with reduced catalytic activities. 758 59

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

There is evidence for a 37% deficiency of complex I activity in Parkinson's disease (PD), which appears to be specific for PD amongst parkinsonian syndromes and selective for the substantia nigra within the central nervous system. Rat studies have shown that, in the context of a normal nigrostriatal dopaminergic cell population, L-dihydroxyphenylalanine (L-dopa) causes a reversible 25% defect of complex I activity in nigral and striatal tissue. Analysis of striatal tissue from PD patients after prolonged exposure to high-dose L-dopa does not show such a defect. Results of these and other studies suggest that L-dopa therapy does not cause complex I deficiency in PD striatum. However, it cannot be excluded that, in the particular environment of the PD substantia nigra, L-dopa may enhance a preexisting complex I defect.
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PMID:L-dihydroxyphenylalanine and complex I deficiency in Parkinson's disease brain. 765 46

Alterations in complex I activity, one of the enzymatic units of the mitochondrial respiratory chain, have been demonstrated in different tissues from patients with Parkinson's disease (PD). Subsequently, we showed that the chronic administration of levodopa can cause alterations in mitochondrial respiratory chain activity in rats, which suggests that the observed deficit in complex I activity in PD might be, at least in part, related to chronic levodopa therapy. Our study assessed the in vitro effects of different antiparkinsonian agents on complex I activity in rat brain. As previously reported, both levodopa and dopamine inhibit complex I activity in a dose-dependent manner. In contrast, the two major metabolites of dopamine, homovanillic acid and 3,4-dihydroxyphenylacetic acid as well as 3-O-methyl-dopa, had little or no effect on complex I activities. Bromocriptine, pergolide, trihexyphenidyl, molindone, and clozapine were all without significant inhibitory effects on mitochondrial function. Although vitamin C and deprenyl did not alter complex I activity, they did prevent the inhibitory effect of both levodopa and dopamine on complex I activity. This work indicates that among the different and usual antiparkinsonian agents, only levodopa and dopamine induced reductions in complex I activity. It also indicates that vitamin C and deprenyl are both effective in preventing the levodopa-induced complex I inhibition. This latter finding provides further support to the use of antioxidants and monoamine oxidase inhibitors as therapeutic strategies in attempts to slow the progression of PD.
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PMID:Antiparkinsonian therapies and brain mitochondrial complex I activity. 765 49

Defects in complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH) occur in the substantia nigra in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) are implicated in the cause of PD as endogenous toxins and are inhibitors of complex I. However, their effects on alpha-KGDH and other mitochondrial non-respiratory chain enzymes are unknown. We have examined the effects of six isoquinoline derivatives (isoquinoline, N-methylisoquinolinium, N-n-propylisoquinolinium, 1,2,3,4-tetrahydroisoquinoline, N-methyl-1,2,3,4-tetrahydroisoquinoline and salsolinol) and MPP+ on the activities of alpha-KGDH, citrate synthase (CS) and glutamate dehydrogenase (GDH) in mitochondrial fragments from rat forebrain. None of the compounds examined had any effect on CS or GDH activity. In contrast, all isoquinoline derivatives investigated and MPP+ inhibited alpha-KGDH activity in a concentration-dependent manner with IC50s ranging from 2.0 to 18.9 mM. MPP+ was previously shown to inhibit alpha-KGDH, but this is the first report of inhibition of alpha-KGDH by isoquinoline derivatives. These findings may represent an additional mechanism contributing to mitochondrial dysfunction and cell death in Parkinson's disease.
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PMID:Inhibition of alpha-ketoglutarate dehydrogenase by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 766 87

Work on the molecular mechanisms of MPTP neurotoxicity have inspired search into the function of mitochondria in idiopathic Parkinson's disease. All the studies show a decrease of 30 to 40% in the activity of the respiratory complex I in the mitochondria of the nigra substantia. This decreased activity is not found in other degenerative Parkinsonisms treated with L-Dopa and cannot be explained simply by age. It is not found in other tissues including muscles and platelets. The causal mechanism of this mitochondrial dysfunction is unknown but it is not related to a mutation in mitochondrial DNA.
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PMID:[Idiopathic Parkinson disease and mitochondrial functions]. 767 50


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