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)

Substantia nigra pars compacta of seven patients who had died of Parkinson's disease, has been investigated for the iron-depending aconitase (reactions I and II). In addition we analysed respiratory chain enzymes. While complex I activity of the respiratory chain was significantly reduced, other enzymes of this pathway were unaltered. The citric acid cycle enzyme aconitase (reactions I and II) showed no difference between patients and controls. Thus this ferrous iron dependent and oxidatively sensitive enzyme is not affected by the unphysiological high amount of ferric iron and the 'oxidative stress' present in substantia nigra of parkinsonian patients.
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PMID:Unaltered aconitase activity, but decreased complex I activity in substantia nigra pars compacta of patients with Parkinson's disease. 804 66

We have cloned and characterized the ACO2 gene on human chromosome 22q13, which encodes the essential iron-dependent metabolic enzyme mitochondrial aconitase. We determined that the ACO2 gene comprises 18 translated exons distributed over approximately 35 kilobasepairs (kbp) of DNA. We have shown that the ACO2 mRNA is 2.7kb in length and is expressed ubiquitously, and we can detect multiple isoforms of the ACO2 protein. As others had reported the existence of biochemically active electrophoretic variants of mitochondrial aconitase, we wished to find common ACO2 gene allozymes, functional polymorphisms that might be associated with susceptibility to human genetic diseases. We looked for ACO2 allozymes by DNA sequencing and genotyping in a population of 217 subjects, many of which had idiopathic Parkinson's disease (IPD). We studied patients with IPD because this movement disorder is thought to arise from defects in neuronal iron and energy metabolism, two properties with which aconitase is involved. Furthermore, reports of associations between alleles of the CYP2D6 locus (nearby on 22q13) and IPD, although inconsistent, indicated that an IPD susceptibility locus might be in strong linkage disequilibrium with CYP2D6. We found three functionally silent single nucleotide polymorphisms (SNPs) present in transcribed sequences that exist in similar frequencies in IPD patients and healthy controls. These ACO2 SNPs are in linkage disequilibrium with each other, providing evidence for distinct ACO2 haplotypes. We have, as yet, not detected polymorphisms that would lead to ACO2 allozymes, nor have we observed differences in ACO2 isoform prevalence or distribution in our population of IPD patients and controls. We conclude it is unlikely that polymorphism in the ACO2 gene or post-translational modification of the enzyme predispose to IPD.
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PMID:Characterization of the human mitochondrial aconitase gene (ACO2). 963 Jun 32

The symptoms of Mn-induced neurotoxicity resemble those of Parkinson's diseases. Since iron (Fe) appears to play a pivotal role in pathophysiology of Parkinson's disease, we set out to test the hypothesis that alterations in Fe-requiring enzymes such as aconitase contribute to Mn-induced neurotoxicity. Mitochondrial fractions prepared from rat brain were preincubated with MnCl2 in vitro, followed by the enzyme assay. Mn treatment significantly inhibited mitochondrial aconitase activity (24% inhibition at 625 microM to 81% at 2.5 mM, p<0.05). The inhibitory effect was reversible and Mn-concentration dependent, and was reversed by the addition of Fe (0.05-1 mM) to the reaction mixture. In an in vivo chronic Mn exposure model, rats received intraperitoneal injection of 6 mg/kg Mn as MnCl2 once daily for 30 consecutive days. Mn exposure led to a region-specific alteration in total aconitase (i.e. , mitochondrial+cytoplasmic): 48.5% reduction of the enzyme activity in frontal cortex (p<0.01), 33.7% in striatum (p<0.0963), and 20.6% in substantia nigra (p<0.139). Chronic Mn exposure increased Mn concentrations in serum, CSF, and brain tissues. The elevation of Mn in all selected brain regions (range between 3.1 and 3.9 fold) was similar in magnitude to that in CSF (3.1 fold) rather than serum (6. 1 fold). The present results suggest that Mn alters brain aconitase activity, which may lead to the disruption of mitochondrial energy production and cellular Fe metabolism in the brain.
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PMID:Manganese inhibits mitochondrial aconitase: a mechanism of manganese neurotoxicity. 967 33

The alpha-ketoglutarate dehydrogenase complex (KGDHC) is an important mitochondrial constituent, and deficiency of KGDHC is associated with a number of neurological disorders. KGDHC is composed of three proteins, each encoded on a different and well-characterized gene. The sequences of the human proteins are known. The organization of the proteins into a large, ordered multienzyme complex (a "metabolon") has been well studied in prokaryotic and eukaryotic species. KGDHC catalyzes a critical step in the Krebs tricarboxylic acid cycle, which is also a step in the metabolism of the potentially excitotoxic neurotransmitter glutamate. A number of metabolites modify the activity of KGDHC, including inactivation by 4-hydroxynonenal and other reactive oxygen species (ROS). In human brain, the activity of KGDHC is lower than that of any other enzyme of energy metabolism, including phosphofructokinase, aconitase, and the electron transport complexes. Deficiencies of KGDHC are likely to impair brain energy metabolism and therefore brain function, and lead to manifestations of brain disease. In general, the clinical manifestations of KGDHC deficiency relate to the severity of the deficiency. Several such disorders have been recognized: infantile lactic acidosis, psychomotor retardation in childhood, intermittent neuropsychiatric disease with ataxia and other motor manifestations, Friedreich's and other spinocerebellar ataxias, Parkinson's disease, and Alzheimer's disease (AD). A KGDHC gene has been associated with the first two and last two of these disorders. KGDHC is not uniformly distributed in human brain, and the neurons that appear selectively vulnerable in human temporal cortex in AD are enriched in KGDHC. We hypothesize that variations in KGDHC that are not deleterious during reproductive life become deleterious with aging, perhaps by predisposing this mitochondrial metabolon to oxidative damage.
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PMID:The alpha-ketoglutarate dehydrogenase complex. 1067 30

The central nervous system has a particularly high energy requirement, thus making it very susceptible to defects in mitochondrial function. A number of neurodegenerative diseases, in particular Parkinson's disease (PD), Huntington's disease (HD) and Friedreich's ataxia (FRDA), are associated with mitochondrial dysfunction. The identification of a mitochondrial complex-I defect in PD provides a link between toxin models of the disease, and clues to the pathogenesis of idiopathic PD. We have undertaken genomic transplantation studies involving the transfer of mitochondrial DNA (mtDNA) from PD patients with a complex-I defect to a novel nuclear background. Histochemical, immunohistochemical and functional analysis of the resulting cybrids all showed a pattern in the PD clones indicative of a mtDNA mutation. There is good evidence for the involvement of defective energy metabolism and excitotoxicity in the aetiology of HD. We, and others, have shown a severe deficiency of complex II/III confined to the striatum that mimics the toxin-induced animal models of HD. There is also a milder defect in complex IV in the caudate. The tricarboxylic acid cycle enzyme aconitase is particularly sensitive to inhibition by peroxynitrite and superoxide radicals. We have found this enzyme to be severely decreased in HD caudate, putamen and cortex in a pattern that parallels the severity of neuronal loss seen. We propose a scheme for the role of nitric oxide, free radicals and excitotoxicity in the pathogenesis of HD. FRDA is caused by an expanded GAA repeat in intron 1 of the X25 gene encoding a protein called frataxin. Frataxin is widely expressed and is a mitochondrial protein, although its function is unknown. We have found abnormal magnetic resonance spectroscopy in the skeletal muscle of FRDA patients, which parallels our biochemical findings of reduced complexes I-III in patients' heart and skeletal muscle. There is also reduced aconitase activity in these areas. Increased iron deposition was seen in patients' tissues in a pattern consistent with a mitochondrial location. The mitochondrial iron accumulation, defective respiratory chain activity and aconitase dysfunction suggest that frataxin may be involved in mitochondrial iron regulation. There is also evidence that oxidative stress contributes to cellular toxicity.
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PMID:Secondary abnormalities of mitochondrial DNA associated with neurodegeneration. 1098 61

In this study reactive oxygen species (ROS) generated in the respiratory chain were measured and the quantitative relationship between inhibition of the respiratory chain complexes and ROS formation was investigated in isolated nerve terminals. We addressed to what extent complex I, III and IV,respectively, should be inhibited to cause ROS generation. For inhibition of complex I, III and IV, rotenone, antimycin and cyanide were used, respectively, and ROS formation was followed by measuring the activity of aconitase enzyme. ROS formation was not detected until complex III was inhibited by up to 71 +/- 4%, above that threshold inhibition, decrease in aconitase activity indicated an enhanced ROS generation. Similarly, threshold inhibition of complex IV caused an accelerated ROS production. By contrast, inactivation of complex I to a small extent (16 +/- 2%) resulted in a significant increase in ROS formation, and no clear threshold inhibition could be determined. However, the magnitude of ROS generated at complex I when it is completely inhibited is smaller than that observed when complex III or complex IV was fully inactivated. Our findings may add a novel aspect to the pathology of Parkinson's disease, showing that a moderate level of complex I inhibition characteristic in Parkinson's disease leads to significant ROS formation. The amount of ROS generated by complex I inhibition is sufficient to inhibit in situ the activity of endogenous aconitase.
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PMID:Quantitative relationship between inhibition of respiratory complexes and formation of reactive oxygen species in isolated nerve terminals. 1248 7

1-Methyl-4-phenylpyridinium (MPP(+)) is a neurotoxin used in cellular models of Parkinson's Disease. Although intracellular iron plays a crucial role in MPP(+)-induced apoptosis, the molecular signalling mechanisms linking iron, reactive oxygen species (ROS) and apoptosis are still unknown. We investigated these aspects using cerebellar granule neurons (CGNs) and human SH-SY5Y neuroblastoma cells. MPP(+) enhanced caspase 3 activity after 24 h with significant increases as early as 12 h after treatment of cells. Pre-treatment of CGNs and neuroblastoma cells with the metalloporphyrin antioxidant enzyme mimic, Fe(III)tetrakis(4-benzoic acid)porphyrin (FeTBAP), completely prevented the MPP(+)-induced caspase 3 activity as did overexpression of glutathione peroxidase (GPx1) and pre-treatment with a lipophilic, cell-permeable iron chelator [N, N '-bis-(2-hydroxybenzyl)ethylenediamine-N, N '-diacetic acid, HBED]. MPP(+) treatment increased the number of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labelling)-positive cells which was completely blocked by pre-treatment with FeTBAP. MPP(+) treatment significantly decreased the aconitase and mitochondrial complex I activities; pre-treatment with FeTBAP, HBED and GPx1 overexpression reversed this effect. MPP(+) treatment increased the intracellular oxidative stress by 2-3-fold, as determined by oxidation of dichlorodihydrofluorescein and dihydroethidium (hydroethidine). These effects were reversed by pre-treatment of cells with FeTBAP and HBED and by GPx1 overexpression. MPP(+)-treatment enhanced the cell-surface transferrin receptor (TfR) expression, suggesting a role for TfR-induced iron uptake in MPP(+) toxicity. Treatment of cells with anti-TfR antibody (IgA class) inhibited MPP(+)-induced caspase activation. Inhibition of nitric oxide synthase activity did not affect caspase 3 activity, apoptotic cell death or ROS generation by MPP(+). Overall, these results suggest that MPP(+)-induced cell death in CGNs and neuroblastoma cells proceeds via apoptosis and involves mitochondrial release of ROS and TfR-dependent iron.
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PMID:1-Methyl-4-phenylpyridinium (MPP+)-induced apoptosis and mitochondrial oxidant generation: role of transferrin-receptor-dependent iron and hydrogen peroxide. 1252 38

1-Methyl-4-phenylpyridinium (MPP(+)) is a neurotoxin that causes Parkinson's disease in experimental animals and humans. Despite the fact that intracellular iron was shown to be crucial for MPP(+)-induced apoptotic cell death, the molecular mechanisms for the iron requirement remain unclear. We investigated the role of transferrin receptor (TfR) and iron in modulating the expression of alpha-synuclein (alpha-syn) in MPP(+)-induced oxidative stress and apoptosis. Results show that MPP(+) inhibits mitochondrial complex-1 and aconitase activities leading to enhanced H(2)O(2) generation, TfR expression and alpha-syn expression/aggregation. Pretreatment with cell-permeable iron chelators, TfR antibody (that inhibits TfR-mediated iron uptake), or transfection with glutathione peroxidase (GPx1) enzyme inhibits intracellular oxidant generation, alpha-syn expression/aggregation, and apoptotic signaling as measured by caspase-3 activation. Cells overexpressing alpha-syn exacerbated MPP(+) toxicity, whereas antisense alpha-syn treatment totally abrogated MPP(+)-induced apoptosis in neuroblastoma cells without affecting oxidant generation. The increased cytotoxic effects of alpha-syn in MPP(+)-treated cells were attributed to inhibition of mitogen-activated protein kinase and proteasomal function. We conclude that MPP(+)-induced iron signaling is responsible for intracellular oxidant generation, alpha-syn expression, proteasomal dysfunction, and apoptosis. Relevance to Parkinson's disease is discussed.
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PMID:Alpha-synuclein up-regulation and aggregation during MPP+-induced apoptosis in neuroblastoma cells: intermediacy of transferrin receptor iron and hydrogen peroxide. 1474 48

Alpha synuclein protein may play an important role in familial and sporadic Parkinson's disease pathology. We have induced G209A mutant or wild-type alpha-synuclein expression in stable HEK293 cell models to determine if this influences markers of oxidative stress and damage under normal conditions or in the presence of dopamine or paraquat. Induced wild-type or mutant alpha-synuclein expression alone had no effect upon levels of oxidative stress or damage, as measured by glutathione levels or aconitase activity. Both wild-type and mutant alpha-synuclein expression decreased the oxidative damage induced by paraquat, although the protection was less marked with mutant alpha-synuclein expression. This suggests that alpha-synuclein expression may either have anti-oxidant properties or may upregulate cellular antioxidant levels, a function that was diminished by the G209A mutation. However, mutant but not wild-type alpha-synuclein expression specifically enhanced dopamine associated oxidative damage. Non-expressing cells treated with reserpine to inhibit the vesicular monoamine compartmentalisation produced similar results. However, consistent with the hypothesis that mutant alpha-synuclein disrupts vesicular dopamine compartmentalization, this effect was diminished in cells expressing mutant alpha-synuclein. This may result in increased dopamine metabolism and cause selective oxidative damage to dopaminergic cells.
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PMID:G209A mutant alpha synuclein expression specifically enhances dopamine induced oxidative damage. 1523 9

We have investigated the ability of pramipexole, a dopamine agonist used in the symptomatic treatment of Parkinson's disease (PD), to protect against cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and rotenone in dopaminergic and non-dopaminergic cells. Pre-incubation with either the active (-)- or inactive (+)-enantiomer forms of pramipexole (10 microm) decreased cell death in response to MPP+ and rotenone in dopaminergic SHSY-5Y cells and in non-dopaminergic JK cells. The protective effect was not prevented by dopamine receptor blockade using sulpiride or clozapine. Protection occurred at concentrations at which pramipexole did not demonstrate antioxidant activity, as shown by the failure to maintain aconitase activity. However, pramipexole reduced caspase-3 activation, decreased the release of cytochrome c and prevented the fall in the mitochondrial membrane potential induced by MPP+ and rotenone. This suggests that pramipexole has anti-apoptotic actions. The results extend the evidence for the neuroprotective effects of pramipexole and indicate that this is not dependent on dopamine receptor occupation or antioxidant activity. Further evaluation is required to determine whether the neuroprotective action of pramipexole is translated to a disease-modifying effect in PD patients.
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PMID:Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms. 1556 51


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