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)

Some studies have demonstrated that the motor symptomatology in sporadic and familial Parkinson's disease was identical. From a physiopathological point of view, and perhaps in the future from a therapeutic point of view, it seems important to determine whether sporadic and familial Parkinson's disease are also similar with regard to cognitive impairment. The aim of the present study was to assess cognitive functions in patients suffering from sporadic and familial Parkinson's disease. Executive functions and memory were investigated in particular. Two groups of 12 patients with Parkinson's disease (sporadic and familial) and 12 healthy controls performed a set of tasks known to evaluate different aspects of executive function and memory. One-way analysis of variance tested for significant group effects, and when justified, post hoc analysis was performed. Cognitive impairment was different in sporadic and familial forms of Parkinson's disease. Indeed, although executive function was impaired in both groups of patients, deficits in tests of explicit memory recall were only observed in patients with sporadic Parkinson's disease. Although the impairment observed in both groups of patients suggests a disruption of the striatoprefrontal circuits, this disruption seems to be quantitatively more important and more widespread in the sporadic patients than in the familial ones. In both patient groups, the deficits probably result from dopaminergic and nondopaminergic deprivation and a greater participation of nondopaminergic factors in patients with sporadic Parkinson's disease could be suggested. In this group, a xenobiotic could be responsible for an acquired metabolic defect involving more widespread structures of the striatoprefrontal circuits, leading to disruption of nondopaminergic loops. Cholinergic deprivation is considered in particular.
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PMID:Memory and executive function in sporadic and familial Parkinson's disease. 1115 66

The role of xenobiotic metabolising enzymes (XMEs) in disease aetiology has been under investigation by numerous researchers around the world for the last two decades. The association of a number of defects in both phase I and phase II reactions with Parkinson's disease (PD) and motor neuron disease (MND) have been extensively studied. This review of the work of the group based initially at the University of Birmingham into the functional genomics of XMEs and neurodegenerative diseases has indicated that: 1. Sub-groups of patients with PD and MND can be identified with problems in xenobiotic metabolism by in vivo or in vitro methods. 2. 38-39% of the patients with MND/PD have a defect in the S-oxidation of the mucoactive drug, carbocysteine, by an unknown cytosolic oxidase(s). The odds risk ratio for the association of this defect with these diseases was calculated to be 10.21 for MND and 10.50 for PD. 3. Patients with PD appear to have an altered substrate specificity for monoamine oxidase B substrates in an in vitro platelet assay. 4. Patients with MND have an increased capacity to S-methylate aliphatic sulphydryl compounds in an in vivo challenge as well as an in vitro erythrocyte thiol methyltransferase assay. The results of over a decade of investigations into both PD and MND indicate that these are diseases with mutifactorial origins that encompass both genetic predisposition and environmental insult.
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PMID:A review of xenobiotic metabolism enzymes in Parkinson's disease and motor neuron disease. 1146 Aug 78

Oxidative stress is hypothesized to play a major role in the destruction of dopaminergic neurons, which is associated with Parkinson's disease. Epoxides are potentially reactive intermediates formed through the oxidative metabolism of both exogenous and endogenous substances that contribute to cytotoxic damage mediated by oxidative stress. The microsomal (EPHX1) and soluble (EPHX2) epoxide hydrolases function to regulate the oxidation status of a wide range of xenobiotic- and lipid-derived substrates; therefore, interindividual variation in these pathways may mitigate epoxide-related cellular injury. In this investigation, we examined the potential association between the risk of Parkinson's disease and genetic variation within the EPHX1 and EPHX2 genes. Fluorescent 5' nuclease-based assays were developed to identify the allelic status of individuals with respect to specific single nucleotide polymorphisms in exons 3 and 4 of the EPHX1 gene and exons 8 and 13 of the EPHX2 gene. EPHX1 and EPHX2 genotype data were obtained from 133 idiopathic Parkinson's disease patients and 212 control subjects matched on age, gender and ethnicity. No statistically significant differences were found in the distribution of the reference and variant alleles between Parkinson's disease and control subjects, or when results were stratified by gender. Therefore, common polymorphisms within EPHX1 and EPHX2 do not appear to be important risk factors for Parkinson's disease.
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PMID:Genetic polymorphisms of microsomal and soluble epoxide hydrolase and the risk of Parkinson's disease. 1169 79

Parkinson's disease (PD) is a common neurodegenerative disease characterized by dopaminergic cell death and deposition of Lewy bodies within the substantia nigra of the midbrain. Although the major risk factors for PD are aging and environmental factors, there is an important genetic component. An age-related change in xenobiotic metabolism alters the metabolism of and net exposure to, environmental neurotoxins. Genetic variability in xenobiotic metabolism may similarly increase the susceptibility to PD by altering the metabolism of neurotoxins. Genetic studies of rare familial cases of PD indicate a central mechanistic role for the aggregation of alpha-synuclein, a protein found in Lewy bodies. Environmental factors like pesticides and heavy metals can also influence alpha-synuclein aggregation. Common final pathways for aging, environmental, and genetic mechanisms can thus exist, involving both direct neurotoxicity and alpha-synuclein aggregation.
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PMID:Age-environment and gene-environment interactions in the pathogenesis of Parkinson's disease. 1208 93

Relatively early seminal investigations on 'mammalian alkaloid biosynthesis'-endogenous Pictet-Spengler condensations of catecholamines or indoleamines with aldehydes (such as acetaldehyde from ethanol metabolism) to form tetrahydroisoquinoline or beta-carboline alkaloids-and the roles of mammalian alkaloids in the CNS complications of chronic alcoholism were launched in Gerald Cohen's laboratory. While occasional studies on alcohol and the alkaloids continue today, the field of study has been expanded principally by others into Parkinson's disease. Certain mammalian or xenobiotic alkaloids have been examined by various laboratories as possible neurotoxic factors inducing mitochondrial energy depletion and/or oxidative stress in the nigrostriatum. In that regard, specific arguments for N-methylated 'MPP(+)-like' cationic alkaloids that can be generated centrally from beta-carbolines derived from the environment and diet are summarized.
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PMID:Alkaloids, alcohol and Parkinson's disease. 1221 30

Retrospective case-control studies among patients with idiopathic Parkinson's syndrome (IPS) show a positive association to the existence of a - mostly premorbid - exposure to pesticides. In acute pesticide intoxications, usually symptoms other than parkinsonism are found. Therefore, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) continues to be the agent best documented both experimentally and clinically to cause a clinical syndrome comparable to IPS. It is debated whether still unknown effects between exogenous pesticide exposure and the xenobiotic enzyme system may lead to IPS in single genetically susceptible individuals. In practice, the present data on the problem of pesticide exposure in IPS are irrelevant for medicolegal considerations.
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PMID:[Pesticide exposure and Parkinson's syndrome - the epidemiological and experimental evidence]. 1237 87

The finding that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicits parkinsonism in human beings suggests that endogenous or xenobiotic neurotoxic compounds may be involved in the etiology of Parkinson's disease (PD). We have shown that cerebrospinal fluid (CSF) of newly diagnosed and drug untreated patients with PD contains a low molecular weight substance(s) which inhibits the growth and function of dopaminergic neurons in culture. In addition, selegiline in a dosage below the level that inhibits monoamine oxidase B (MAO-B), protects dopaminergic neurons in culture against toxic factor(s) present in the CSF of patients with PD, and the said effect is mediated via elaboration of brain-derived neurotrophic factor (BDNF). In view of the fact that 6-hydroxydopamine (6-OHDA) or MPTP causes parkinsonism by generating free radicals, and inducers of metallothionein (MT) isoforms avert the said neurotoxicity, we intended to learn whether MT isoforms were capable of scavenging free radicals. By employing electron spin resonance spectroscopy (ESR), we examined for the first time the free radical scavenging effects of MT-I and MT-II isoforms on four types of free radicals. Solutions of 0.15 mM of MT-I and 0.3 mM of MT-II scavenged the 1,1-diphenyl-2-picrylhydrazyl radicals completely. Furthermore, they were able to scavenge hydroxyl radicals generated in a Fenton reaction. Moreover, MT-I scavenged almost 90% of the superoxide generated by the hypoxanthine and xanthine oxidase system, while MT-II could only scavenge 40%. By using 2,2,6,6-tetramethyl-4-piperidone as a "spin-trap" for the reactive oxygen species (containing singlet oxygen, superoxide and hydroxyl radicals) generated by photosensitized oxidation of riboflavin, and measuring the relative signal intensities of the resulting stable nitroxide adduct, 2,2,6,6-tetramethyl-4-piperidone-1-oxyl, we observed that MT-II could scavenge 92%, while MT-I could completely scavenge all the reactive species generated. The results of this investigation are interpreted to suggest that selegiline by preventing the generation of free radicals, MT isoforms by scavenging free radicals, and neurotrophins by rescuing dopaminergic neurons are capable of attenuating oxidative stress and of providing neuro-protection in PD.
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PMID:Metallothionein, neurotrophins and selegiline in providing neuroprotection in Parkinson's disease. 1267 4

The role of defective 'sulphur xenobiotic' biotransformations in the aetiology of Parkinson's and motor neurone diseases has been in the literature for over a decade. Problems in the S-oxidation of aliphatic thioethers, sulphation of phenolic compounds and the S-methylation of aliphatic sulphydryl groups have all been reported. These reports have also been consistent in observing that only a 'significant minority' of patients express these problems in sulphur biotransformation pathways. However, no investigation has yet reported on the incidence of these three defective pathways in control invididuals and in patients with Parkinson's and motor neurone disease. This investigation has found that: 1. Forty percent of patients with Parkinson's and motor neurone disease have a defect in the S-oxidation of S-carboxymethyl-L-cysteine compared to 4% of controls. 2. 35-40% of patients with Parkinson's and motor neurone disease have a defect in the sulphation of paracetamol compared to 4% of controls. 3. 60% of patients with motor neurone disease have a high capacity for the S-methylation of 2-mercaptoethanol compared to 4% of controls. 4. 38% of patients with Parkinson's disease have a low capacity for the S-methylation of 2-mercaptoethanol compared to 4% of controls. 5. There is no correlation between the S-oxidation phenotype, low paracetamol sulphation phenotype and low or high S-methylation phenotype in controls or patients with Parkinson's or motor neurone disease. 6. The number of controls that expressed one of the aberrant phenotypes was 4% compared to 38% of the patients with Parkinson's disease and 47% of the patients with motor neurone disease. 7. The number of controls that expressed two of the aberrant phenotypes was 0% compared to 18% of the patients with Parkinson's disease and 19% of those with motor neurone disease. 8. No controls or patients with Parkinson's disease or motor neurone disease expressed all three of the aberrant phenotypes. The results indicate that the three xeno-biotransformation pathways are under separate genetic control in the three population groups studied and that patients with Parkinson's and motor neurone disease do not have a widespread defect in their sulphur xenobiochemistry capacity.
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PMID:An investigation into the inter-relationships of sulphur xeno-biotransformation pathways in Parkinson's and motor neurone diseases. 1476 72

Parkinson's disease may be a disease of autointoxication. N-methylated pyridines (e.g. MPP+) are well-established dopaminergic toxins, and the xenobiotic enzyme nicotinamide N-methyltransferase (NNMT) can convert pyridines such as 4-phenylpyridine into MPP+, using S-adenosyl methionine (SAM) as the methyl donor. NNMT has recently been shown to be present in the human brain, a necessity for neurotoxicity, because charged compounds cannot cross the blood-brain barrier. Moreover, it is present in increased concentration in parkinsonian brain. This increase may be part genetic predisposition, and part induction, by excessive exposure to its substrates (particularly nicotinamide) or stress. Elevated enzymic activity would increase MPP+-like compounds such as N-methyl nicotinamide at the same time as decreasing intraneuronal nicotinamide, a neuroprotectant at several levels, creating multiple hits, because Complex 1 would be poisoned and be starved of its major substrate NADH. Developing xenobiotic enzyme inhibitors of NNMT for individuals, or dietary modification for the whole population, could be an important change in thinking on primary and secondary prevention.
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PMID:Parkinson's disease: the first common neurological disease due to auto-intoxication? 1572 3

Parkinson's disease (PD) is a common, progressive, incurable disabling condition. The cause is unknown but over the past few years tremendous progress in our understanding of the genetic bases of this condition has been made. To date, this has almost exclusively come from the study of relatively rare Mendelian forms of the disease and there are no currently, widely accepted common variants known to increase susceptibility. The role that the "Mendelian" genes play in common sporadic forms of PD is unknown. Moreover, most studies in PD can really be described as candidate polymorphism studies rather than true and complete assessments of the genes themselves. We provide a model of how one might tackle some of these issues using Parkinson's disease as an illustration. One of the emerging hypotheses of gene environment interaction in Parkinson's disease is based on drug metabolizing (or xenobiotic) enzymes and their interaction with putative environmental toxins. This motivated us to describe a tagging approach for an extensive but not exhaustive list of 55 drug metabolizing enzyme genes. We use these data to illustrate the power, and some of the limitations of a haplotype tagging approach. We show that haplotype tagging is extremely efficient and works well with only a modest increase in effort through different populations. The tagging approach works much less well if the minor allele frequency is below 5%. However, it will now be possible using these tags to evaluate these genes comprehensively in PD and other neurodegenerative conditions.
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PMID:Population genetic approaches to neurological disease: Parkinson's disease as an example. 1609 6


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