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)

Oxidative stress may contribute to the progression of Parkinson's disease, and while the status of antioxidant enzymes is thus important, little data on their regional distribution in basal ganglia exist. We now report on the distribution and levels of messenger ribonucleic acid (m-RNA) for the antioxidant enzymes copper, zinc-superoxide dismutase (Cu,Zn-SOD), manganese-superoxide dismutase (Mn-SOD), and glutathione peroxidase in rat basal ganglia using in situ hybridisation histochemistry with complementary deoxyribonucleic acid probes specific for these enzymes. The m-RNA for Cu,Zn-SOD, Mn-SOD, and glutathione peroxidase was expressed throughout basal ganglia. Levels of m-RNA were significantly higher in substantia nigra pars compacta than in all other regions of basal ganglia for both Cu,Zn-SOD (53-62%, P<0.001) and Mn-SOD (37-45%, P<0.05). Mn-SOD m-RNA levels were also significantly higher in SN pars reticulata than in the nucleus accumbens (10%, P<0.05) and striatum (12%, P<0.01). In contrast, glutathione peroxidase m-RNA levels were only significantly higher in SN pars compacta when compared with SN pars reticulata (23%, P<0.05), and in the striatum when compared with the nucleus accumbens (21%, P<0.05). The data suggest that SN pars compacta may be vulnerable to oxidative stress and thus dependent on the high antioxidant capacity provided by these cytoprotective enzymes. In conclusion, this study demonstrates the relative distribution of antioxidant enzymes in rat basal ganglia and forms the basis for further study in rodent models of Parkinson's disease.
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PMID:The distribution of copper, zinc- and manganese-superoxide dismutase, and glutathione peroxidase messenger ribonucleic acid in rat basal ganglia. 1193 49

Aluminum and zinc have been related to the pathogenesis of Parkinson's disease (PD), the former for its neurotoxicity and the latter for its apparent antioxidant properties. 6-Hydroxydopamine (6-OHDA) is an important neurotoxin putatively involved in the pathogenesis of PD, its neurotoxicity often being related to oxidative stress. The potential effect of these metals on the oxidative stress induced by 6-OHDA autoxidation and the potential of ascorbic acid (AA), cysteine, and glutathione to modify this effect were investigated. Both metals, particularly Al3+, induced a significant reduction in *OH production by 6-OHDA autoxidation. The combined action of AA and a metal caused a significant and sustained increase in *OH generation, particularly with Al3+, while the effect of sulfhydryl reductants was limited to only the first few minutes of the reaction. However, both Al3+ and Zn2+ provoked a decrease in the lipid peroxidation induced by 6-OHDA autoxidation using mitochondrial preparations from rat brain, assessed by TBARS formation. In the presence of AA, only Al3+ induced a significant reduction in lipid peroxidation. After intrastriatal injections of 6-OHDA in rats, tyrosine hydroxylase immunohistochemistry revealed that Al3+ reduces 6-OHDA-induced dopaminergic lesion in the striatum, which corroborates the involvement of lipid peroxidation in 6-OHDA neurotoxicity and appears to discard the participation of this mechanism on PD by Al3+ accumulation. The previously reported antioxidant properties of Zn2+ appear to be related to the induction of Zn2+-containing proteins and not to the metal per se.
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PMID:Effects of aluminum and zinc on the oxidative stress caused by 6-hydroxydopamine autoxidation: relevance for the pathogenesis of Parkinson's disease. 1195 57

Dithiocarbamate (DTC)-based pesticides have been implicated in Parkinson's disease (PD) through epidemiological links to increased risk of PD, clinical reports of parkinsonism following occupational exposure to the DTC-based pesticide maneb, and experimental studies showing dopaminergic neurodegeneration with combined exposure of rats to maneb and paraquat. We hypothesize that the manganese-ethylene-bis-dithiocarbamate (MnEBDC) complex in maneb may produce oxidative stress by catalyzing catechol oxidation. We tested this hypothesis by performing a structure-function analysis of metal-EBDC and metal-diethyldithiocarbamate (DEDC) complexes of Mn2+, Zn2+, and Cu2+ to catalyze oxidation of N-acetyldopamine (NA-DA) and 3,4-dihydroxyphenylacetic acid (DP) in the presence and absence of N-acetylcysteine (NAC), a model of glutathione. Both Mn-DTCs retained the capacity of the parent ion to catalyze one-electron oxidation of NA-DA, but lost the ability to catalyze DP oxidation. Strikingly, while Zn2+ did not catalyze catechol oxidation, both Zn-DTCs catalyzed one-electron oxidation of NA-DA but not DP. While Cu2+ catalyzed oxidation of both catechols, Cu-DTCs were inert. Similar results were obtained with MnEBDC and dopamine or norepinephrine; however, zinc-ethylene-bis-dithiocarbamate was less efficient at catalyzing oxidation of these catechols. Our results point to the potential for manganese- and zinc-containing EBDC pesticides to promote oxidative stress in catecholaminergic regions of the brain.
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PMID:Catalysis of catechol oxidation by metal-dithiocarbamate complexes in pesticides. 1248 39

Alterations occurring in the antioxidant enzymes, copper, zinc-dependent superoxide dismutase (Cu,Zn-SOD) and glutathione peroxidase (GPX) following nigral dopaminergic denervation are unclear. We now report on the distribution and levels of m-RNA for Cu,Zn-SOD and GPX in basal ganglia of normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, and in normal individuals and patients with Parkinson's disease (PD) using in situ hybridization histochemistry and oligodeoxynucleotide (single-stranded DNA) probes. Cu,Zn-SOD and GPX m-RNA was present throughout basal ganglia (nucleus accumbens, caudate-putamen, globus pallidus, substantia nigra) in the common marmoset, with the highest levels being in substantia nigra (SN). Following MPTP induced nigral cell loss, Cu,Zn-SOD m-RNA levels were decreased in all areas but the SNr, and particularly in SNc (71%, P<0.001). MPTP-treatment had no effect on GPX m-RNA expression in any area of basal ganglia. Cu,Zn-SOD and GPX m-RNA was also present in the normal human SN. In PD, however, Cu,Zn-SOD m-RNA was significantly decreased (89%, P<0.005) in SNc, and there was a near-complete loss of GPX m-RNA in both SNc (100%, P<0.005) and SNr (88%, P<0.005). The loss of Cu,Zn-SOD m-RNA in SNc in MPTP-treated marmosets and patients with PD suggests that it is primarily located in dopaminergic neuronal cell bodies. The loss of GPX m-RNA in SNc in PD also suggests a localisation to dopaminergic cell bodies, but the similar change in SNr may indicate its presence in dopaminergic neurites. In contrast, the absence of change in GPX m-RNA in MPTP-treated primates appears to rule out its presence in dopaminergic cells in this species, but this may only be apparent and may reflect increased expression in glial cells following acute toxin treatment.
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PMID:Alterations in m-RNA expression for Cu,Zn-superoxide dismutase and glutathione peroxidase in the basal ganglia of MPTP-treated marmosets and patients with Parkinson's disease. 1266 90

The aggregation and fibrillation of alpha-synuclein has been implicated as a key step in the etiology of Parkinson's disease and several other neurodegenerative disorders. In addition, oxidative stress and certain environmental factors, including metals, are believed to play an important role in Parkinson's disease. Previously, we have shown that methionine-oxidized human alpha-synuclein does not fibrillate and also inhibits fibrillation of unmodified alpha-synuclein (Uversky, V. N., Yamin, G., Souillac, P. O., Goers, J., Glaser, C. B., and Fink, A. L. (2002) FEBS Lett. 517, 239-244). Using dynamic light scattering, we show that the inhibition results from stabilization of the monomeric form of Met-oxidized alpha-synuclein. We have now examined the effect of several metals on the structural properties of methionine-oxidized human alpha-synuclein and its propensity to fibrillate. The presence of metals induced partial folding of both oxidized and non-oxidized alpha-synucleins, which are intrinsically unstructured under conditions of neutral pH. Although the fibrillation of alpha-synuclein was completely inhibited by methionine oxidation, the presence of certain metals (Ti3+, Zn2+, Al3+, and Pb2+) overcame this inhibition. These findings indicate that a combination of oxidative stress and environmental metal pollution could play an important role in triggering the fibrillation of alpha-synuclein and thus possibly Parkinson's disease.
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PMID:Certain metals trigger fibrillation of methionine-oxidized alpha-synuclein. 1275 58

Parkinson's disease 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 have 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 against peroxynitrite-induced neurodegeneration in Parkinson's disease. 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 enhanced the synthesis of 8-hydroxy-2-deoxyguanosine. Furthermore, it down-regulated the expression of Bcl-2 and poly(ADP-ribose) polymerase, but up-regulated 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 to dihydroxyphenylacetaldehyde was attenuated in metallothionein-transgenic fetal stem cells and in cells transfected with a mitochondrial genome, and 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 down-regulation of a mitochondrial genome and up-regulation of caspase-3 as determined by reverse transcription-polymerase chain reaction. The synthesis of mitochondrial 8-hydroxy-2-deoxyguanosine and apoptosis-inducing factors were increased following exposure to 1-methyl-4-phenylpyridinium ion or rotenone. Pretreatment with selegiline or metallothionein suppressed 1-methyl-4-phenylpyridinium ion-, 6-hydroxydopamine-, and rotenone-induced increases in mitochondrial 8-hydroxy-2-deoxyguanosine accumulation. Transfection of aging mitochondrial genome knockout neurons with mitochondrial genome encoding complex-1 or melanin attenuated the SIN-1-induced increase in lipid peroxidation. SIN-1 induced the expression of alpha-synuclein, caspase-3, and 8-hydroxy-2-deoxyguanosine, and augmented protein nitration. These effects were attenuated by metallothionein gene overexpression. These studies provide evidence that nitric oxide synthase activation and peroxynitrite ion overproduction may be involved in the etiopathogenesis of Parkinson's disease, and that metallothionein gene induction may provide neuroprotection.
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PMID:Metallothionein attenuates 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in dopaminergic neurons. 1288 Apr 80

The aetiology of Parkinson's disease (PD) is unknown and said to be multifactorial. We report on a retrospective epidemiological case control study, performed in Flanders during a 3-year period, investigating known and potential environmental risk factors for PD by means of questionnaires. We investigated 423 prevalent patients and 205 spouse-controls. We found familial occurrence in 15% of the patients, a mean age of onset of 58 years, and a clear male preponderance (male/female ratio 1.53). Our results suggest more nulliparity among female PD patients (95% CI: 1.08-5.76). We found a discrete clustering of patients in areas with intensive metallurgic frequently employed in metallurgy than controls (95% CI: 1.04-9.20). Furthermore, patients were clearly more exposed to zinc (95% CI: 1.51-90.90) and toluene (95% CI: 1.03 58.82). Male patients report more prostatectomy-surgery (95% CI: 1.54-17.24).
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PMID:Case-control study of environmental risk factors for Parkinson's disease in Belgium. 1475 67

The aggregation of normally soluble alpha-synuclein in the dopaminergic neurons of the substantia nigra is a crucial step in the pathogenesis of Parkinson's disease. Oxidative stress is believed to be a contributing factor in this disorder. We have previously established that oxidation of all four methionine residues in alpha-synuclein (to the sulfoxide, MetO) inhibits fibrillation of this protein in vitro and that the MetO protein also inhibits fibrillation of unmodified alpha-synuclein. Here we show that the degree of inhibition of fibrillation by MetO alpha-synuclein is proportional to the number of oxidized methionines. This was accomplished be selectively converting Met residues into Leu, prior to Met oxidation. The results showed that with one oxidized Met the kinetics of fibrillation were comparable to those for the control (nonoxidized), and with increasing numbers of methionine sulfoxides the kinetics of fibrillation became progressively slower. Electron microscope images showed that the fibril morphology was similar for all species examined, although fewer fibrils were observed with the oxidized forms. The presence of zinc was shown to overcome the Met oxidation-induced inhibition. Interestingly, substitution of Met by Leu led to increased propensity for aggregation (soluble oligomers) but slower formation of fibrils.
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PMID:Role of individual methionines in the fibrillation of methionine-oxidized alpha-synuclein. 1507 9

In this study, a comparative analysis of metal-related neuronal vulnerability was performed in two brainstem nuclei, the locus coeruleus (LC) and substantia nigra (SN), known targets of the etiological noxae in Parkinson's disease and related disorders. LC and SN pars compacta neurons both degenerate in Parkinson's disease and other Parkinsonisms; however, LC neurons are comparatively less affected and with a variable degree of involvement. In this study, iron, copper, and their major molecular forms like ferritins, ceruloplasmin, neuromelanin (NM), manganese-superoxide dismutase (SOD), and copper/zinc-SOD were measured in LC and SN of normal subjects at different ages. Iron content in LC was much lower than that in SN, and the ratio heavy-chain ferritin/iron in LC was higher than in the SN. The NM concentration was similar in LC and SN, but the iron content in NM of LC was much lower than SN. In both regions, heavy- and light-chain ferritins were present only in glia and were not detectable in neurons. These data suggest that in LC neurons, the iron mobilization and toxicity is lower than that in SN and is efficiently buffered by NM. The bigger damage occurring in SN could be related to the higher content of iron. Ferritins accomplish the same function of buffering iron in glial cells. Ceruloplasmin levels were similar in LC and SN, but copper was higher in LC. However, the copper content in NM of LC was higher than that of SN, indicating a higher copper mobilization in LC neurons. Manganese-SOD and copper/zinc-SOD had similar age trend in LC and SN. These results may explain at least one of the reasons underlying lower vulnerability of LC compared to SN in Parkinsonian syndromes.
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PMID:The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. 1521 Sep 60

Trace metals such as zinc, manganese, and iron are necessary for the growth and function of the brain. The transport of trace metals into the brain is strictly regulated by the brain barrier system, i.e., the blood-brain and blood-cerebrospinal fluid barriers. Trace metals usually serve the function of metalloproteins in neurons and glial cells, while a portion of trace metals exists in the presynaptic vesicles and may be released with neurotransmitters into the synaptic cleft. Zinc and manganese influence the concentration of neurotransmitters in the synaptic cleft, probably via the action against neurotransmitter receptors and transporters and ion channels. Zinc may be an inhibitory neuromodulator of glutamate release in the hippocampus, while neuromodulation by manganese might mean functional and toxic aspects in the synapse. Dietary zinc deficiency affects zinc homeostasis in the brain, followed by an enhanced susceptibility to the excitotoxicity of glutamate in the hippocampus. Transferrin may be involved in the physiological transport of iron and manganese into the brain and their utilization there. It is reported that the brain transferrin concentration is decreased in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease and that brain iron metabolism is also altered. The homeostasis of trace metals in the brain is important for brain function and also for the prevention of brain diseases.
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PMID:[Essential trace metals and brain function]. 1534 Jan 79


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