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)

In a population-based case-control study, we investigated the potential role of occupational exposure to iron, copper, manganese, mercury, zinc, and lead as risk factors for Parkinson's disease (PD). Concurrently recruited, nondemented patients (n = 144) with idiopathic PD and controls (n = 464) consisting of men and women > or =50 years of age, frequency-matched for age (within 5 years), race, and sex were enrolled. All had primary medical care at Henry Ford Health System in urban/suburban metropolitan Detroit. Subjects were given an extensive risk-factor questionnaire detailing actual worksite conditions of all jobs held for more than 6 months from age 18 onward. An industrial hygienist, blinded to the case-control status of subjects, rated occupational exposure to each of the metals of interest. When adjusted for sex, race, age, and smoking status, we found in those with more than 20 years' exposure a significantly increased association with PD for copper (OR = 2.49, 95% CI = 1.06, 5.89) and manganese (OR = 10.61, 95% CI = 1.06, 105.83). For more than 20 years' exposure to combinations of lead-copper (OR = 5.24, 95% CI = 1.59, 17.21), lead-iron (OR = 2.83, 95% CI = 1.07, 7.50), and iron-copper (OR = 3.69, 95% CI = 1.40, 9.71), there was a greater association with PD than with any of these metals alone. These findings suggest that chronic exposure to these metals is associated with PD, and that they may act alone or together over time to help produce the disease.
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PMID:Occupational exposures to metals as risk factors for Parkinson's disease. 906 42

Zinc is an important trace element in biology. An important pool of zinc in the brain is the one present in synaptic vesicles in a subgroup of glutamatergic neurons. In this form it can be released by electrical stimulation and may serve to modulate responses at receptors for a number of different neurotransmitters. These include both excitatory and inhibitory receptors, particularly the NMDA and GABA(A) receptors. This pool of zinc is the only form of zinc readily stained histochemically (the chelatable zinc pool), but constitutes only about 8% of the total zinc content in the brain. The remainder of the zinc is more or less tightly bound to proteins where it acts either as a component of the catalytic site of enzymes or in a structural capacity. The metabolism of zinc in the brain is regulated by a number of transport proteins, some of which have been recently characterized by gene cloning techniques. The intracellular concentration may be mediated both by efflux from the cell by the zinc transporter ZrT1 and by complexing with apothionein to form metallothlonein. Metallothionein may serve as the source of zinc for incorporation into proteins, including a number of DNA transcription factors. However, zinc is readily released from metallothionein by disulfides, increasing concentrations of which are formed under oxidative stress. Metallothionein is a very good scavenger of free radicals, and zinc itself can also reduce oxidative stress by binding to thiol groups, decreasing their oxidation. Zinc is also a very potent inhibitor of nitric oxide synthase. Increased levels of chelatable zinc have been shown to be present in cell cultures of immune cells undergoing apoptosis. This is very reminiscent of the zinc staining of neuronal perikarya dying after an episode of ischemia or seizure activity. Thus a possible role of zinc in causing neuronal death in the brain needs to be fully investigated. intraventricular injections of calcium EDTA have already been shown to reduce neuronal death after a period of ischemia. Pharmacological doses of zinc cause neuronal death, and some estimates indicate that extracellular concentrations of zinc could reach neurotoxic levels under pathological conditions. Zinc is released in high concentrations from the hippocampus during seizures. Unfortunately, there are contrasting observations as to whether this zinc serves to potentiate or decrease seizure activity. Zinc may have an additional role in causing death in at least some neurons damaged by seizure activity and be involved in the sprouting phenomenon which may give rise to recurrent seizure propagation in the hippocampus. In Alzheimer's disease, zinc has been shown to aggregate beta-amyloid, a form which is potentially neurotoxic. The zinc-dependent transcription factors NF-kappa B and Sp1 bind to the promoter region of the amyloid precursor protein (APP) gene. Zinc also inhibits enzymes which degrade APP to nonamyloidogenic peptides and which degrade the soluble form of beta-amyloid. The changes in zinc metabolism which occur during oxidative stress may be important in neurological diseases where oxidative stress is implicated, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Zinc is a structural component of superoxide dismutase 1, mutations in which give rise to one form of familiar ALS. After HIV infection, zinc deficiency is found which may be secondary to immune-induced cytokine synthesis. Zinc is involved in the replication of the HIV virus at a number of sites. These observations should stimulate further research into the role of zinc in neuropathology.
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PMID:Zinc metabolism in the brain: relevance to human neurodegenerative disorders. 936 Dec 93

We compared CSF and serum levels of iron, copper, manganese, and zinc, measured by atomic absorption spectrophotometry, in 37 patients with Parkinson's disease (PD) and 37 matched controls. The CSF levels of zinc were significantly decreased in PD patients as compared with controls (p < 0.05). The serum levels of zinc, and the CSF and serum levels of iron, copper, and manganese, did not differ significantly between PD-patient and control groups. There was no influence of antiparkinsonian therapy on CSF levels of none of these transition metals. These values were not correlated with age, age at onset, duration of the disease, scores of the Unified Parkinson Disease Rating Scale of the Hoehn and Yahr staging in the PD group, with the exception of CSF copper levels with the duration of the disease (r = 0.38, p < 0.05). These results suggest that low CSF zinc concentrations might be related with the risk for PD, although they could be related with oxidative stress processes.
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PMID:Cerebrospinal fluid levels of transition metals in patients with Parkinson's disease. 972 Sep 77

It is an increasingly popular hypothesis that the continued degeneration of dopaminergic neurons in Parkinson's disease (PD) may be the consequence of aberrant oxidation of dopamine and resultant generation of DNA reactive species in PD patients receiving levodopa (l-DOPA) therapy. Occupational metal exposure, particularly to manganese, is a risk factor for Parkinsonism and manganese has been shown to be a true catalyst for dopamine oxidation lending support to this hypothesis. In the present studies, we demonstrate that the antiproliferative activity of l-DOPA and dopamine on Chinese Hamster V79 cells is enhanced by at least an order of magnitude by concomitant exposure to manganese chloride or copper sulfate (500 microM), but not to iron(III) or zinc. Moreover, manganese and copper confer strong clastogenic properties to both compounds as detected in an in vitro micronucleus assay in V79 cells. Metal catalyzed oxidation of drug was associated with the development of a brown-black particulate substance presumed to be a melanin precursor formation. The extent of formation of this precursor paralleled clastogenicity. Metal-enhanced effects were completely antagonized by the concurrent addition of cysteine or reduced glutathione to the cultures. These findings are in support of the hypothesis that aberrant oxidation of dopamine resulting from non-physiological levels of catalytic metals may contribute to the death of dopaminergic neurons and further suggest that oxidation-dependent DNA damage may be the basis for this cell death.
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PMID:Enhancement of cytotoxicity and clastogenicity of l-DOPA and dopamine by manganese and copper. 972 32

One of the primary areas of investigation in the pathophysiology of Parkinson's disease (PD) is the loss of the dopamine-producing cells in the melanized neurons of the substantia nigra, believed to be caused by oxidative stress resulting from excessive free radical activity. The cuprozinc enzyme, superoxide dismutase (SODCu2Zn2), catalyzes the dismutation of superoxide anions to hydrogen peroxide plus oxygen, and is normally found in high concentrations in the substantia nigra where it protects neurons by scavenging free radicals. Zinc supplementation has been shown to significantly increase SODCu2Zn2 in vitro. A novel oral zinc tally test (ZTT) used in the assessment of zinc status was administered to 100 PD patients and 25 controls. Patients with PD showed a significantly decreased zinc status as compared to controls (p < 0.001). Significance was also established for 3 self-reported health-related variables thought to be related to zinc status: vision problems, olfactory loss, and taste loss (p < 0.05). Relative risks for patients with PD for these variables were 1.51, 1.56, and 1.33, respectively. Zinc status as measured by the ZTT is negatively correlated with PD status. PD status is positively correlated with self-reported vision problems, and olfactory and taste loss. Further study of the role of zinc in the development and treatment of PD is warranted.
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PMID:Evidence of functional zinc deficiency in Parkinson's disease. 1010 31

Manganese toxicity has been associated with clinical symptoms of neurotoxicity which are similar to the symptoms observed in Parkinson's disease. Earlier reports indicated that reactive microglia was present in the substantia nigra of patients with Parkinson's disease. Using N9 microglial cells, the current study was designed to determine whether high levels of manganese were associated with microglial activation. Results indicated that manganese significantly increased the bacterial lipopolysaccharide-induced nitric oxide production. This potent activity of manganese was not shared by other transition metals tested, including iron, cobalt, nickel, copper and zinc. Immunohistochemical staining and Western blot analysis indicated that manganese increased the cellular production of inducible nitric oxide synthase. Northern blot analysis indicated that manganese likely increased iNOS gene transcription since this agent increased the mRNA level of the inducible nitric oxide synthase. In contrast to other transition metals tested, manganese did not appear to be cytotoxic to microglial cells. These results suggested that manganese could induce sustained production of neurotoxic nitric oxide by activated microglial cells, which might cause detrimental consequences to surrounding neurons.
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PMID:Manganese potentiates nitric oxide production by microglia. 1032 Jul 80

A population-based case-control study was conducted in the Henry Ford Health System (HFHS) in metropolitan Detroit to assess occupational exposures to manganese, copper, lead, iron, mercury and zinc as risk factors for Parkinson's disease (PD). Non-demented men and women 50 years of age who were receiving primary medical care at HFHS were recruited, and concurrently enrolled cases (n = 144) and controls (n = 464) were frequency-matched for sex, race and age (+/- 5 years). A risk factor questionnaire, administered by trained interviewers, inquired about every job held by each subject for 6 months from age 18 onward, including a detailed assessment of actual job tasks, tools and environment. An experienced industrial hygienist, blinded to subjects' case-control status, used these data to rate every job as exposed or not exposed to one or more of the metals of interest. Adjusting for sex, race, age and smoking status, 20 years of occupational exposure to any metal was not associated with PD. However, more than 20 years exposure to manganese (Odds Ratio [OR] = 10.61, 95% Confidence Interval [CI] = 1.06, 105.83) or copper (OR = 2.49, 95% CI = 1.06,5.89) was associated with PD. Occupational exposure for > 20 years to combinations of lead-copper (OR = 5.24, 95% CI = 1.59, 17.21), lead-iron (OR = 2.83, 95% CI = 1.07,7.50), and iron-copper (OR = 3.69, 95% CI = 1.40,9.71) was also associated with the disease. No association of occupational exposure to iron, mercury or zinc with PD was found. A lack of statistical power precluded analyses of metal combinations for those with a low prevalence of exposure (i.e., manganese, mercury and zinc). Our findings suggest that chronic occupational exposure to manganese or copper, individually, or to dual combinations of lead, iron and copper, is associated with PD.
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PMID:Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson's disease. 1038 87

In recent studies, we have found a marked increase in substantia nigra (SN) echogenicity in patients with Parkinson's disease (PD) using transcranial ultrasound. Because a substantial body of evidence has accumulated indicating a selective elevation of iron in the SN from patients with PD, we set out to test the hypothesis that trace metals like iron could lead to the observed increase of SN echogenicity in PD. Rat brains were scanned after stereotactic injection of iron in different concentrations into the SN and after injecting ferritin, zinc and 6-OHDA alone, and after the addition of desferrioxamine. The amount of iron in the SN was measured spectroscopically. For iron, and partly for 6-OHDA, in different concentrations, a dose-dependent increase of SN echogenicity could be visualized, corresponding to an increase of iron measured by spectroscopy. No increase of echogenicity was visualized after the injection of ferritin and the addition of desferrioxamine to 6-OHDA, though an increase of iron was measured by spectroscopy. Therefore, we conclude that iron not bound to these proteins may lead to an increase of echogenicity of the SN.
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PMID:Iron accumulation in the substantia nigra in rats visualized by ultrasound. 1046 17

Genetic transfer approaches have received recent consideration as potential treatment modalities for human central and peripheral nervous system (CNS and PNS, respectively) neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Transplantation of genetically modified cells into the brain represents a promising strategy for the delivery and expression of specific neurotrophic factors, neurotransmitter-synthesizing enzymes, and cellular regulatory proteins for intervention in neurodegenerative diseases. The use of specific regulatable promoters may also provide potential control of gene expression required for dose-specific or time-specific therapeutic strategies. In this article, we review the potential use of activated promoters in ex vivo systems for the potential genetic therapy of neurodegenerative disorders, and then describe our own studies using the zinc-inducible metallothionein promoter for the regulated expression of nerve growth factor (NGF) in rodent brain transplants.
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PMID:Promoter-activated expression of nerve growth factor for treatment of neurodegenerative diseases. 1051 13

Occupational exposure to specific metals (manganese, copper, lead, iron, mercury, zinc, aluminum and others) appears to be a risk factor for Parkinson's disease (PD) in some, but not all, case-control studies. These epidemiological studies are reviewed. Several methodological issues that may account for the lack of unanimity of findings are discussed, and suggestions for improved case-control methodology are offered. The study of the neurological disease outcome of workers who have had long-term, well-defined occupational exposure to one or more metals is also urged, with collaborative work including industrial hygienists, occupational toxicologists, neurologists, epidemiologists and biostatisticians. Such efforts, employing state-of-the-art case and control ascertainment and enrollment from suitable population bases, neurological diagnostic rigor and exposure assessment, will help to further define the potentially important roles played by metals in PD and other neurodegenerative disorders.
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PMID:Occupational metal exposures and the risk of Parkinson's disease. 1054 82


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