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)

Bromocriptine, a dopamine D2 receptor agonist, has widely been used for patients with Parkinson's disease. In this study, we examined its neuroprotective effects against neuronal damage in the CA1 subfield of the hippocampus following experimental cerebral ischemia in the Mongolian gerbil. Forebrain ischemia was induced by occlusion of bilateral common carotid arteries for 3 min. Bromocriptine, at a dose of 0.3 or 3 mg/kg, was injected i.p. 30 min before the onset of ischemia. Histopathological observations showed that neuronal damage to hippocampal CA1 neurons, which was seen 7 days after ischemia in vehicle-treated animals, was prevented by bromocriptine treatment. Immunohistochemical staining for copper/zinc superoxide dismutase and manganese superoxide dismutase decreased markedly in the CA1 neurons of vehicle-treated animals 2 days after ischemia when histological neuronal destruction was not yet seen, but was well preserved in bromocriptine-treated animals. The present findings show that bromocriptine protects against ischemia-induced neuronal damage, and that the mechanism of the neuroprotection may relate to the preservation of SODs. Bromocriptine, which was recently shown to be a potent free radical scavenger, may have a potent neuroprotective action against disorders including ischemic stroke.
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PMID:Bromocriptine protects against delayed neuronal death of hippocampal neurons following cerebral ischemia in the gerbil. 775 51

Mitochondrial targeting sequence (MTS) has a common property to form an amphiphilic helical structure which is essential for its effective transport of mitochondrial protein. Natural polymorphism in human MTS which affects its mitochondrial transport ability has not been reported. Furthermore, no structural polymorphism for manganese superoxide dismutase (MnSOD) gene has been studied in human population. We here identify diallelic polymorphism (Ala-9Val) in the MTS of human MnSOD in a Japanese population. Calculation of a helix forming potential predicted the typical amphiphilic helical structure in -9Ala allele and its disruption in -9Val allele. We here suggest that this mutation may reflect functional polymorphism of mitochondrial transport of human MnSOD. An association study using this polymorphism showed significant allelic deviation for -9Ala allele (12.1% vs. 19.3%) in Parkinson's disease.
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PMID:Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson's disease. 880 73

We report an immunohistochemical study on manganese superoxide dismutase (Mn SOD) in Parkinson's disease (PD) patients and age-matched control subjects. Overall appearance of immunostaining intensity of nigral neurons did not differ significantly between the PD patients and the control subjects. However, when the immunostaining intensity of each neuron was semiquantitatively analyzed, both very intensely stained (more than normal) neurons as well as neurons stained only weakly were more frequently detected in the lateral part than in the medial and the central parts of the substantia nigra in PD patients. As a result, the proportion of normally stained neurons was significantly smaller in the lateral part of the substantia nigra in PD patients; however, the overall distribution of the neurons among the three rating grades for immunostaining did not differ significantly. The immunostaining intensity of the neuropils in the medial and the central part of the substantia nigra tended to be more intense in PD patients than in the control subjects. Our results suggest up-regulation of Mn SOD mainly in the dendritic processes of the less involved nigral neurons.
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PMID:An immunohistochemical study on manganese superoxide dismutase in Parkinson's disease. 912 14

Parkinson disease (PD) is a common neurodegenerative condition associated with degeneration of dopaminergic neurons in the zona compacta of the substantia nigra. There is increasing evidence that genetic factors play a role in the etiology of PD, although genetic heterogeneity is likely. An autosomal dominant syndrome with many similarities to sporadic PD has been mapped to 4q21-22 in a large Italian pedigree and has been found to be due to mutation of the alpha-synuclein gene. However, this gene appears to account for only a minority of PD, and a susceptibility locus for autosomal dominant parkinsonism has recently been mapped, on 2p13. Autosomal recessive juvenile parkinsonism (JP), which shows marked clinical similarity to PD, maps to 6q25.2-q27. We found linkage to this region in a group of 15 families from four distinct ethnic backgrounds. A full genomic screen excluded other candidate regions. We have constructed a detailed genetic map of the linked region and have mapped the position of the manganese superoxide dismutase gene (SOD2). Recombination events restricted the JP locus to a 6.9-cM region and excluded SOD2. The apparent homozygosity for null alleles at D6S955 in one family suggested a deletion and finer localization of the JP locus.
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PMID:Autosomal recessive juvenile parkinsonism maps to 6q25.2-q27 in four ethnic groups: detailed genetic mapping of the linked region. 963 34

Peroxynitrite can nitrate tyrosine residues of proteins. We examined nitrotyrosine-containing proteins in cerebrospinal fluid of 66 patients with neurogenic disease by immunoblot analysis. Nitrated tyrosine residue-containing protein was observed in the cerebrospinal fluid and was concluded to be manganese superoxide dismutase (Mn-SOD). The nitrated Mn-SOD level was strikingly elevated in amyotrophic lateral sclerosis patients and was slightly increased in Alzheimer's and Parkinson's disease patients, whereas an elevated Mn-SOD level was observed only in progressive supranuclear palsy group.
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PMID:Nitration of manganese superoxide dismutase in cerebrospinal fluids is a marker for peroxynitrite-mediated oxidative stress in neurodegenerative diseases. 1076 67

Oxidative stress reactions may contribute to the pathogenesis of Parkinson's disease (PD). The superoxide dismutases potentially play significant roles in PD by detoxifying superoxide radical. We developed genomic DNA and cDNA-based sequencing assays to identify genetic variants in the copper/zinc superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2) genes. No genetic variants were detected in the gene encoding SOD1 in DNA from 45 idiopathic PD cases and 49 controls from a population-based case-control study. However, we identified a previously described polymorphism of the mitochondrial targeting sequence consisting of a C47T in exon 2 of SOD2, which results in an alanine to valine substitution. We analyzed this SOD2 variant in DNA from 155 cases and 231 controls from the same study, using an allele-specific fluorogenic 5' nuclease assay, and found no differences in the distributions of allelic frequencies. These results indicate that SOD gene variants do not contribute to PD pathogenesis.
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PMID:Genetic polymorphisms of superoxide dismutase in Parkinson's disease. 1148 95

Dopaminergic neurons of the substantia nigra are susceptible to toxin-based insults. Intrastriatal injection of 6-hydroxydopamine results in selective toxicity to these neurons. A mechanistic role for reactive oxygen species is supported by observations that antioxidants confer protection from 6-hydroxydopamine. Although cell culture studies have suggested extracellular or nonmitochondrial mechanisms in 6-hydroxydopamine toxicity, the compartmentalization of oxidative injury mechanisms is incompletely defined in vivo. Transgenic mice overexpressing mitochondrial manganese superoxide dismutase or extracellular superoxide dismutase received unilateral intrastriatal injections of 6-hydroxydopamine. Mice that overexpress manganese superoxide dismutase showed significantly smaller striatal lesions than littermate controls. There were no differences in nonspecific striatal injury associated with contralateral vehicle injection. Manganese superoxide dismutase overexpression also protected against loss of neuronal cell bodies in the substantia nigra. In contrast, mice overexpressing extracellular superoxide dismutase showed no protection from 6-hydroxydopamine toxicity in either brain region. Protection of the nigrostriatal system by overexpression of manganese superoxide dismutase supports a role for mitochondrially derived superoxide in 6-hydroxydopamine toxicity. Mitochondrial oxidative stress appears to be a common mechanism among diverse models of Parkinson disease, whether involving toxins, mutated genes, or cybrid cells containing patient mitochondria. Antioxidant therapies that target this subcellular compartment may prove promising.
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PMID:Manganese superoxide dismutase protects against 6-hydroxydopamine injury in mouse brains. 1575 37

Oxidative stress has been well documented in the substantia nigra in Parkinson disease (PD), but little is known about oxidative damage, particularly lipoxidation, advanced glycation (AGE), and AGE receptors (RAGE) in other structures, including the cerebral cortex, in early stages of diseases with Lewy bodies. The present study was undertaken to analyze these parameters in the frontal cortex (area 8), amygdala, and substantia nigra in selected cases with no neurologic symptoms and with neuropathologically verified incidental Lewy body disease-related changes, comparing them with healthy age-matched individuals. Results of the present study have shown mass spectrometric and immunologic evidences of increased lipoxidative damage by the markers malondialdehyde-lysine (MDAL) and 4-hydroxynonenal-lysine (HNE), increased expression of AGE in the substantia nigra, amygdala, and frontal cortex, and increased and heterogeneous RAGE cellular expression in the substantia nigra and frontal cortex in cases with early stages of parkinsonian neuropathology. In addition, increased content of the highly peroxidizable docosahexaenoic acid in the amygdala and frontal cortex. These changes were not associated to alpha-synuclein aggregation in cortex, contrasting with aggregates found in SDS-soluble fractions of frontal cortex in dementia with Lewy bodies (DLB) cases. The pattern of lipidic abnormalities differed in DLB and incidental Lewy body disease. Furthermore, although AGE and RAGE expression were raised in DLB, no increase in the total amount of HNE and MDAL adducts was found in the cerebral cortex in DLB. Preliminary analyses have identified 2 proteins with lipoxidative damage, alpha-synuclein and manganese superoxide dismutase (SOD2), in incidentally Lewy body disease cortex. This study demonstrates abnormal fatty acid profiles, increased and selective lipoxidative damage, and increased AGE and RAGE expression in the frontal cortex in cases with early stages of parkinsonian neuropathology without treatment. These findings further support antioxidant therapy in the treatment of PD to reduce cortical damage associated with oxidative stress.
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PMID:Evidence of oxidative stress in the neocortex in incidental Lewy body disease. 1614 92

Parkinson's disease (PD) is a common neurodegenerative disorder that results from the selective loss of midbrain dopaminergic neurons. Misfolding and aggregation of the protein alpha-synuclein, oxidative damage, and proteasomal impairment are all hypotheses for the molecular cause of this selective neurotoxicity. Here, we describe a Saccharomyces cerevisiae model to evaluate the misfolding, aggregation, and toxicity-inducing ability of wild-type alpha-synuclein and three mutants (A30P, A53T, and A30P/A53T), and we compare regulation of these properties by dysfunctional proteasomes and by oxidative stress. We found prominent localization of wild-type and A53T alpha-synuclein near the plasma membrane, supporting known in vitro lipid-binding ability. In contrast, A30P was mostly cytoplasmic, whereas A30P/A53T displayed both types of fluorescence. Surprisingly, alpha-synuclein was not toxic to several yeast strains tested. When yeast mutants for the proteasomal barrel (doa3-1) were evaluated, delayed alpha-synuclein synthesis and membrane association were observed; yeast mutant for the proteasomal cap (sen3-1) exhibited increased accumulation and aggregation of alpha-synuclein. Both sen3-1and doa3-1 mutants exhibited synthetic lethality with alpha-synuclein. When yeasts were challenged with an oxidant (hydrogen peroxide), alpha-synuclein was extremely lethal to cells that lacked manganese superoxide dismutase Mn-SOD (sod2Delta) but not to cells that lacked copper, zinc superoxide dismutase Cu,Zn-SOD (sod1Delta). Despite the toxicity, sod2Delta cells never displayed intracellular aggregates of alpha-synuclein. We suggest that the toxic alpha-synuclein species in yeast are smaller than the visible aggregates, and toxicity might involve alpha-synuclein membrane association. Thus, yeasts have emerged effective organisms for characterizing factors and mechanisms that regulate alpha-synuclein toxicity.
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PMID:alpha-Synuclein budding yeast model: toxicity enhanced by impaired proteasome and oxidative stress. 1667 56

Manganese (Mn) is an essential trace nutrient that is potentially toxic at high levels of exposure. As a constituent of numerous enzymes and a cofactor, manganese plays an important role in a number of physiologic processes in mammals. The manganese-containing enzyme, manganese superoxide dismutase (Mn-SOD), is the principal antioxidant enzyme which neutralizes the toxic effects of reactive oxygen species. Other manganese-containing enzymes include oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases and glutamine synthetase. Environmental or occupational exposure to high levels of manganese can cause a neuropathy resembling idiopathic Parkinson's disease, commonly referred to as manganism. Manganism and Parkinson's disease are both characterized by motor deficits and damage to nuclei of the basal ganglia, particularly the substantia nigra, with altered dopamine (and its metabolites) contributing to these disorders. Dopamine, a major neurotransmitter plays a crucial role in the modulation of the cognitive function, working memory and/or attention of the prefrontal cortex and the hippocampus. Dopamine is also a known inhibitory modulator of thyroid stimulating hormone (TSH) secretion. The involvement of dopamine and dopaminergic receptors in neurodevelopment, as well as TSH modulation, led us to hypothesize that excessive manganese exposure may lead to adverse neurodevelopmental outcomes due to the disruption of thyroid homeostasis via the loss of dopaminergic control of TSH regulation of thyroid hormones. This disruption may alter thyroid hormone levels, resulting in some of the deficits associated with gestational exposure to manganese. While the effects of manganese in adult populations are relatively well documented, comprehensive data on its neurodevelopmental effects are sparse. Given the importance of this topic, we review the potential participation of thyroid hormone dyshomeostasis in the neurodevelopmental effects of manganese positing the hypotheses that manganese may directly or indirectly affect thyroid function by injuring the thyroid gland or dysregulating dopaminergic modulation of thyroid hormone synthesis.
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PMID:Effects of manganese on thyroid hormone homeostasis: potential links. 1757 15


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