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)

This article aims to give a broad overview of some of the potential targets for nitric oxide (NO) in the brain. The relevance of NO in both physiological and pathological scenarios is considerable. There is substantial evidence that neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, involve NO in their pathogenesis. Here we describe a number of cellular components which may be affected by NO, with particular relevance to neurological diseases. As the mitochondrion (in particular the electron transport chain) would appear to be of importance when considering the deleterious effects of NO, this review has a particular emphasis on that organelle. Cellular and mitochondrial antioxidants such as glutathione and ubiquinone are also discussed. In addition, the pivotal role of the astrocyte in both neuroprotection or neurodegeneration are examined.
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PMID:Nitric oxide and neurological disorders. 1572 15

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra zona compacta and in other subcortical nuclei associated with a widespread occurrence of Lewy bodies. The causes of cell death in Parkinson's disease are still poorly understood, but a defect in mitochondrial oxidative phosphorylation and enhanced oxidative stress has been proposed. We have examined 3-morpholinosydnonimine (SIN-1)-induced apoptosis in control and metallothionein-overexpressing dopaminergic neurons, with a primary objective to determine the neuroprotective potential of metallothionein (MT) against peroxynitrite-induced neurodegeneration in PD. SIN-1 induced lipid peroxidation and triggered plasma membrane blebbing. In addition, it caused DNA fragmentation, alpha-synuclein induction, and intramitochondrial accumulation of metal ions (copper, iron, zinc, and calcium), and it enhanced the synthesis of 8-hydroxy-2-deoxyguanosine. Furthermore, it downregulated the expression of Bcl-2 and poly(adenosine diphosphate-ribose) polymerase, but upregulated the expression of caspase-3 and Bax in dopaminergic (SK-N-SH) neurons. SIN-1 induced apoptosis in aging mitochondrial genome knockout cells, alpha-synuclein-transfected cells, metallothionein double-knockout cells, and caspase-3-overexpressed dopaminergic neurons. SIN-1-induced changes were attenuated with selegiline or in metallothionein-transgenic striatal fetal stem cells. SIN-1-induced oxidation of dopamine (DA) to dihydroxyphenylacetaldehyde (DopaL) was attenuated in metallothionein-transgenic fetal stem cells and in cells transfected with a mitochondrial genome, and was enhanced in aging mitochondrial genome knockout cells, in metallothionein double-knockout cells, and caspase-3 gene-overexpressing dopaminergic neurons. Selegiline, melatonin, ubiquinone, and metallothionein suppressed SIN-1-induced downregulation of a mitochondrial genome and upregulation of caspase-3 as determined by reverse transcription polymerase chain reaction. These studies provide evidence that nitric oxide synthase activation and peroxynitrite ion overproduction may be involved in the etiopathogenesis of PD, and that metallothionein gene induction may provide neuroprotection.
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PMID:Peroxynitrite in the pathogenesis of Parkinson's disease and the neuroprotective role of metallothioneins. 1629 Dec 39

Degenerative brain disorders (neurodegeneration) can be frustrating for both conventional and alternative practitioners. A more comprehensive, integrative approach is urgently needed. One emerging focus for intervention is brain energetics. Specifically, mitochondrial insufficiency contributes to the etiopathology of many such disorders. Electron leakages inherent to mitochondrial energetics generate reactive oxygen free radical species that may place the ultimate limit on lifespan. Exogenous toxins, such as mercury and other environmental contaminants, exacerbate mitochondrial electron leakage, hastening their demise and that of their host cells. Studies of the brain in Alzheimer's and other dementias, Down syndrome, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, aging, and constitutive disorders demonstrate impairments of the mitochondrial citric acid cycle and oxidative phosphorylation (OXPHOS) enzymes. Imaging or metabolic assays frequently reveal energetic insufficiency and depleted energy reserve in brain tissue in situ. Orthomolecular nutrients involved in mitochondrial metabolism provide clinical benefit. Among these are the essential minerals and the B vitamin group; vitamins E and K; and the antioxidant and energetic cofactors alpha-lipoic acid (ALA), ubiquinone (coenzyme Q10; CoQ10), and nicotinamide adenine dinucleotide, reduced (NADH). Recent advances in the area of stem cells and growth factors encourage optimism regarding brain regeneration. The trophic nutrients acetyl L-carnitine (ALCAR), glycerophosphocholine (GPC), and phosphatidylserine (PS) provide mitochondrial support and conserve growth factor receptors; all three improved cognition in double-blind trials. The omega-3 fatty acid docosahexaenoic acid (DHA) is enzymatically combined with GPC and PS to form membrane phospholipids for nerve cell expansion. Practical recommendations are presented for integrating these safe and well-tolerated orthomolecular nutrients into a comprehensive dietary supplementation program for brain vitality and productive lifespan.
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PMID:Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management. 1636 37

In the present study, we investigated the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on lipoamide dehydrogenase activity and metallothionein content. Lipoamide dehydrogenase is a flavoprotein enzyme, which reduces lipoamide and low molecular weight thiols. This enzyme has also been involved in the conversion of ubiquinone (coenzyme Q-10, oxidized form) to ubiquinol (reduced form). Lipoamide dehydrogenase activity was measured spectrophotometrically following its incubation with different doses of MPTP, MPP+, and divalent metals. MPTP at higher concentrations inhibited the lipoamide dehydrogenase activity, whereas it's potent toxic metabolite 1-methyl-4-phenylpyridinium (MPP+) had a similar effect at lower concentration. Calcium and copper did not affect the enzyme activity at any of the doses tested, whereas, zinc dose dependently enhanced the lipoamide dehydrogenase activity. Additionally, levels of metallothionein in the mouse nigrostriatal system were measured by cadmium affinity method following administration of MPTP. Metallothionein content was significantly reduced in the substantia nigra (SN), and not in the nucleus caudatus putamen (NCP) following a single administration of MPTP (30 mg/kg, i.p.). Our results suggests that both lipoamide dehydrogenase activity and metallothionein levels may be critical for dopaminergic neuronal survival in Parkinson's disease and provides further insights into the neurotoxic mechanisms involved in MPTP-induced neurotoxicity.
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PMID:Role of lipoamide dehydrogenase and metallothionein on 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-induced neurotoxicity. 1776 76

NADH:ubiquinone oxidoreductase (complex I) is an entry point for electrons into the respiratory chain in many eukaryotes. It couples NADH oxidation and ubiquinone reduction to proton translocation across the mitochondrial inner membrane. Because complex I deficiencies occur in a wide range of neuromuscular diseases, including Parkinson's disease, there is a clear need for model eukaryotic systems to facilitate structural, functional and mutational studies. In the present study, we describe the purification and characterization of the complexes I from two yeast species, Pichia pastoris and Pichia angusta. They are obligate aerobes which grow to very high cell densities on simple medium, as yeast-like, spheroidal cells. Both Pichia enzymes catalyse inhibitor-sensitive NADH:ubiquinone oxidoreduction, display EPR spectra which match closely to those from other eukaryotic complexes I, and show patterns characteristic of complex I in SDS/PAGE analysis. Mass spectrometry was used to identify several canonical complex I subunits. Purified P. pastoris complex I has a particularly high specific activity, and incorporating it into liposomes demonstrates that NADH oxidation is coupled to the generation of a protonmotive force. Interestingly, the rate of NADH-induced superoxide production by the Pichia enzymes is more than twice as high as that of the Bos taurus enzyme. Our results both resolve previous disagreement about whether Pichia species encode complex I, furthering understanding of the evolution of complex I within dikarya, and they provide two new, robust and highly active model systems for study of the structure and catalytic mechanism of eukaryotic complexes I.
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PMID:The respiratory complexes I from the mitochondria of two Pichia species. 1945 85

Coenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a number of neuromuscular and neurodegenerative disorders. Primary disorders of CoQ10 biosynthesis are potentially treatable conditions and therefore a high degree of clinical awareness about this condition is essential. A secondary loss of CoQ10 status following HMG-Coa reductase inhibitor (statins) treatment has be implicated in the pathophysiology of the myotoxicity associated with this pharmacotherapy. CoQ10 and its analogue, idebenone, have been widely used in the treatment of neurodegenerative and neuromuscular disorders. These compounds could potentially play a role in the treatment of mitochondrial disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological and muscular diseases, from primary CoQ10 deficiency to neurodegenerative disorders. We also briefly report a case of the myopathic form of CoQ10 deficiency.
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PMID:Coenzyme Q10 in neuromuscular and neurodegenerative disorders. 2001 23

Brain senescence and neurodegeneration occur with a mitochondrial dysfunction characterized by impaired electron transfer and by oxidative damage. Brain mitochondria of old animals show decreased rates of electron transfer in complexes I and IV, decreased membrane potential, increased content of the oxidation products of phospholipids and proteins and increased size and fragility. This impairment, with complex I inactivation and oxidative damage, is named "complex I syndrome" and is recognized as characteristic of mammalian brain aging and of neurodegenerative diseases. Mitochondrial dysfunction is more marked in brain areas as rat hippocampus and frontal cortex, in human cortex in Parkinson's disease and dementia with Lewy bodies, and in substantia nigra in Parkinson's disease. The molecular mechanisms involved in complex I inactivation include the synergistic inactivations produced by ONOO- mediated reactions, by reactions with free radical intermediates of lipid peroxidation and by amine-aldehyde adduction reactions. The accumulation of oxidation products prompts the idea of antioxidant therapies. High doses of vitamin E produce a significant protection of complex I activity and mitochondrial function in rats and mice, and with improvement of neurological functions and increased median life span in mice. Mitochondria-targeted antioxidants, as the Skulachev cations covalently attached to vitamin E, ubiquinone and PBN and the SS tetrapeptides, are negatively charged and accumulate in mitochondria where they exert their antioxidant effects. Activation of the cellular mechanisms that regulate mitochondrial biogenesis is another potential therapeutic strategy, since the process generates organelles devoid of oxidation products and with full enzymatic activity and capacity for ATP production.
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PMID:Brain mitochondrial dysfunction in aging, neurodegeneration, and Parkinson's disease. 2089 Apr 46

NADH dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), encoding a subunit of mitochondrial complex I, is a candidate gene for several neuronal diseases; schizophrenia, bipolar disorder and Parkinson disease (PD). We screened the entire coding region of NDUFV2 in 33 familial PD patients of North African Arab-Berber ethnicity in which all known genetic forms of PD had been excluded. We detected one novel substitution p.K209R (c.626A>G) in one PD proband. Segregation analysis within the family is inconclusive due to small sample size, but consistent with an autosomal dominant mode of inheritance. Subsequent screening of this mutation in ethnically matched sporadic PD patients (n = 238) and controls (n = 371) identified p.K209R in one additional patient. The clinical features of the mutation carriers revealed a mild form of parkinsonism with a prognosis similar to idiopathic PD. Our findings suggest further studies addressing the role of NDUFV2 variation in PD may be warranted.
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PMID:Genetic variation of the mitochondrial complex I subunit NDUFV2 and Parkinson's disease. 2097 73

DJ-1 (PARK7) is a neuroprotective protein that protects cells from oxidative stress. Accordingly, loss-of-function DJ-1 mutations have been linked with a familial form of early onset Parkinson disease. Mechanisms by which DJ-1 level could be enriched in the CNS are poorly understood. Recently we have discovered anti-inflammatory activity of sodium benzoate (NaB), a metabolite of cinnamon and a widely-used food additive. Here we delineate that NaB is also capable of increasing the level of DJ-1 in primary mouse and human astrocytes and human neurons highlighting another novel neuroprotective effect of this compound. Reversal of DJ-1-inducing effect of NaB by mevalonate, farnesyl phosphate, but not cholesterol and ubiquinone, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the induction of DJ-1 by NaB. Accordingly, either an inhibitor of p21(ras) farnesyl protein transferase (FPTI) or a dominant-negative mutant of p21(ras) alone was also able to increase the expression of DJ-1 in astrocytes suggesting an involvement of p21(ras) in DJ-1 expression. However, an inhibitor of geranyl geranyl transferase (GGTI) and a dominant-negative mutant of p21(rac) had no effect on the expression of DJ-1, indicating the specificity of the effect. Similarly lipopolysaccharide (LPS), an activator of small G proteins, also inhibited the expression of DJ-1, and NaB and FPTI, but not GGTI, abrogated LPS-mediated inhibition. Together, these results suggest that NaB upregulates DJ-1 via modulation of mevalonate metabolites and that p21(ras), but not p21(rac), is involved in the regulation of DJ-1.
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PMID:Sodium benzoate, a metabolite of cinnamon and a food additive, upregulates neuroprotective Parkinson disease protein DJ-1 in astrocytes and neurons. 2170 15

A variety of observations support the hypothesis that deficiency of complex I [reduced nicotinamide-adenine dinucleotide (NADH):ubiquinone oxidoreductase] of the mitochondrial respiratory chain plays a role in the pathophysiology of Parkinson's disease (PD). However, recent data from a study using mice with knockout of the complex I subunit NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (Ndufs4) has challenged this concept as these mice show degeneration of non-dopamine neurons. In addition, primary dopamine (DA) neurons derived from such mice, reported to lack complex I activity, remain sensitive to toxins believed to act through inhibition of complex I. We tissue-specifically disrupted the Ndufs4 gene in mouse heart and found an apparent severe deficiency of complex I activity in disrupted mitochondria, whereas oxidation of substrates that result in entry of electrons at the level of complex I was only mildly reduced in intact isolated heart mitochondria. Further analyses of detergent-solubilized mitochondria showed the mutant complex I to be unstable but capable of forming supercomplexes with complex I enzyme activity. The loss of Ndufs4 thus causes only a mild complex I deficiency in vivo. We proceeded to disrupt Ndufs4 in midbrain DA neurons and found no overt neurodegeneration, no loss of striatal innervation and no symptoms of Parkinsonism in tissue-specific knockout animals. However, DA homeostasis was abnormal with impaired DA release and increased levels of DA metabolites. Furthermore, Ndufs4 DA neuron knockouts were more vulnerable to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Taken together, these findings lend in vivo support to the hypothesis that complex I deficiency can contribute to the pathophysiology of PD.
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PMID:Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons. 2209 Apr 23


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