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)

As an animal model of human Parkinson's disease 250 micrograms of 6-Hydroxydopamine was injected intraventricularly in the rats. At 24 h, 48 h, 7th and 14th day after injection, the levels of dopamine, norepinephrine, Cu, Zn- and Mn- superoxide dismutase (SOD), catalase as well as the lipid peroxidative products in the striatum, midbrain and hypothalamus were determined. Our data showed that catecholamines decreased persistently, catalase and Mn-SOD decreased concomitantly, Cu, Zn-SOD, however, remained, unchanged. Lipid peroxidative products increased shortly after injection, then subsided. Our result suggests that lipid peroxidation might be involved in the degenerative process of neurons in Parkinson's disease.
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PMID:[Effect of 6-hydroxydopamine on cerebral catecholamines, lipid peroxidation and antioxidant enzymes in rats-concerned with pathogenesis of Parkinson's disease]. 195 95

Oxidants are ubiquitous in our aerobic environment and could play an etiological role in aging and neurodegenerative diseases such as Alzheimer's disease. All cells contain several antioxidant enzymes, most importantly, superoxide dismutases (MnSOD and CuZnSOD), glutathione peroxidase (GSH-Px), glutathione reductase and catalase. The individual contribution of these antioxidant enzymes in neuronal protection during aging and under in vivo conditions remains unknown. We feel that the use of genetic manipulations to construct cells and/or transgenic mice that specifically overexpress or lack a single function represent a way to an understanding of the role of the individual antioxidant enzymes in neuronal aging. Copper-zinc superoxide dismutase (CuZnSOD) is one of the genes encoded by chromosome 21. As a consequence of gene dosage excess, CuZnSOD activity and protein are increased by 50% in all tissues of Down syndrome (DS) patients. It has been suggested that this increment, by accelerating hydrogen peroxide formation, might promote oxidative damage within DS cells and might be involved in the various neurobiological abnormalities found in DS such as premature aging and Alzheimer-type neurological lesions. Moreover, the level of CuZnSOD protein and mRNA is particularly high in pyramidal hippocampal neurons susceptible to degenerative processes in Alzheimer's disease, and in dopaminergic melanized-neurons vulnerable in Parkinson's disease. In order to test this hypothesis, we have created transfected cells and transgenic mice which express human CuZnSOD gene. An oversupply of this enzyme is not beneficial to the brain of transgenic mice and causes increased thiobarbituric-reactive substances (TBARS), an index of lipid peroxidation, and may be due to peroxides generated by an imbalance between enzymatic activities of CuZnSOD and GSH-Px. Unlike what has been observed in transfected cells with the human CuZnSOD gene, but similar to what was found in the DS fetal brain, the GSH-Px activity was not increased in the brain of transgenic mice. One possibility to explain this discrepancy could be the differential cellular localization of these two enzymes in the brain (CuZnSOD in neurons and GSH-Px in glial cells). This heterogeneous cellular distribution of the enzymes implicated in oxygen-free radicals detoxification could participate to a selective neuronal degeneration. Interestingly, overexpression of CuZnSOD in the brain of transgenic mice is associated with an increased MnSOD activity, the mitochondrial form of the enzyme. This increased MnSOD might be a defense response to protect mitochondria from oxidative damage.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Transgenic mice overexpressing copper-zinc superoxide dismutase: a model for the study of radical mechanisms and aging]. 801 10

Superoxide dismutases (SODs) are metalloenzymes that detoxify superoxide radicals, and occur in cytosolic (Cu,Zn-SOD) and mitochondrial (Mn-SOD) forms in multiple tissues, including brain. A neuroprotective effect against oxide stressor exposures may be provided by SOD, although excessive enzyme activity can produce cell injury by formation of hydroxyl radical from hydrogen peroxide. We measured Cu,Zn-SOD and Mn-SOD activities in peripheral lymphocytes of 43 newly diagnosed idiopathic Parkinson's disease (PD) cases and 62 age- and sex-matched controls free of neurodegenerative disorders. Significant excesses of both SOD forms were found among PD cases compared with controls; however, the excesses were found exclusively among PD patients treated with the monoamine oxidase inhibitor selegiline (L-deprenyl). Enzyme-linked immunosorbent assays (ELISAs) confirmed that the activity excesses were due to increased protein rather than more highly reactive enzymes in lymphocytes of PD cases. Our findings clearly indicate the importance of selegiline on measured Cu,Zn-SOD and Mn-SOD activity in peripheral lymphocytes. Characterizing a possible therapeutic value of SOD will require longitudinal assessments of SOD in relation to PD progression.
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PMID:Selegiline and lymphocyte superoxide dismutase activities in Parkinson's disease. 860 57

Apoptotic, rather than necrotic, nerve cell death now appears as likely to underlie a number of common neurological conditions including stroke, Alzheimer's disease, Parkinson's disease, hereditary retinal dystrophies and Amyotrophic Lateral Sclerosis. Apoptotic neuronal death is a delayed, multistep process and therefore offers a therapeutic opportunity if one or more of these steps can be interrupted or reversed. Research is beginning to show how specific macromolecules play a role in determining the apoptotic death process. We are particularly interested in the critical nature of gradual mitochondrial failure in the apoptotic process and propose that a maintenance of mitochondrial function through the pharmacological modulation of gene expression offers an opportunity for the effective treatment of some types of neurological dysfunction. Our research into the development of small diffusible molecules that reduce apoptosis has grown from studies of the irreversible MAO-B inhibitor (-)-deprenyl. (-)-Deprenyl can reduce neuronal death independently of MAO-B inhibition even after neurons have sustained seemingly lethal damage. (-)-Deprenyl can also influence the process outgrowth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with earlier work of others, we showed that (-)-deprenyl alters the expression of a number of mRNAs or of proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD-2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial membrane potential correlates with mitochondrial ATP production, we have used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl result in a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and decrease cytoplasmic oxidative radical levels and thereby reduces apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may lead to the development of new therapies for neurodegenerative diseases.
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PMID:Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription. 926 33

We report Mn superoxide dismutase (SOD) protein and activity in a patient with familial autosomal recessive Lewy body-negative parkinsonism in comparison with patients with sporadic Parkinson's disease (PD) and controls. We recently proved linkage of this family with markers of chromosome 6 at 6q25.2-27, which included the Mn SOD gene. We used a novel polymorphic mutation at -9 position of the signal peptide of the Mn SOD precursor protein, which caused valine to alanine substitution. All the affected members of this family showed homozygosity for alanine, whereas nonaffected members, sporadic PD patients, and the control subjects studied showed either heterozygosity of alanine and valine or homozygosity of valine. The Mn SOD activity of this familial patient was the highest among the PD patients and the control subjects studied, and an abundant expression of Mn SOD was found in the substantia nigra. The molecular weight of Mn SOD protein by Western blotting of this patient was essentially similar to that of PD patients and the control subjects. High Mn SOD activity may constitute a genetic risk factor in this familial patient. The difference in the signal peptide sequence may affect the expression of Mn SOD within mitochondria; however, it is unlikely that loss of function type Mn SOD mutation is the cause of this familial parkinsonism. Mn SOD in sporadic PD patients was similar to that in controls.
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PMID:Mn SOD activity and protein in a patient with chromosome 6-linked autosomal recessive parkinsonism in comparison with Parkinson's disease and control. 937 4

This review discusses the etiology and pathogenesis of Parkinson's disease (PD). Mitochondrial respiratory failure and oxidative stress appear to be two major contributors to nigral neuronal death in PD. Complex I deficiency has been reported by several groups and appears to be one of the basic abnormalities responsible for mitochondrial failure. The principal question is whether or not complex I deficiency is primary or secondary. The second question is whether or not complex I deficiency is localized in the nigrostriatal system or is systemically present. It is our impression that complex I deficiency is not the primary cause but that its deficiency appears to be systemic. The primary cause may be the combination of genetic background and potential nigral neurotoxins. Exposure of nigral neurons to a high risk for oxidative damage because of its high dopamine content may be the reason for more pronounced nigral complex I deficiency compared to systemic organs. Oxidative stress and mitochondrial failure produce a vicious cycle in nigral neurons. To explore the genetic risk factors of sporadic PD, studies on familial PD and parkinsonism are important. Recently, an autosomal dominant form of familial PD was found to be caused by point mutations of the alpha-synuclein gene, and an autosomal recessive familial parkinsonism was mapped to the long arm of chromosome 6 near the Mn-SOD gene locus. Information obtained in these familial cases will contribute to the research on sporadic PD.
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PMID:Mitochondrial dysfunction in Parkinson's disease. 974 80

Two polymorphisms of the MnSOD gene, Ile58Thr and Ala9Val, have been associated with Parkinson disease (PD). The Ile58Thr amino acid exchange affects the stability at the tetrameric interface of the enzyme and reduces the enzymatic activity of MnSOD while the Ala/Val substitution at position -9 of the mitochondrial targeting sequence (MTS) may lead to misdirected intracellular trafficking. We have analyzed 63 German Caucasian PD patients for possible sequence variation in the MTS as well as in exon 3 of the MnSOD gene. All 63 PD patients analyzed exhibited a T at nucleotide position 5777 in exon 3 of the MnSOD gene corresponding to ATA, or Ile at the peptide level, and no other sequence variants were found. In addition, both alleles of the Ala9Val polymorphism in the MTS of MnSOD were equally distributed between German PD patients and controls excluding this gene variant as a risk factor for PD in Caucasian subjects.
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PMID:Analysis of mitochondrial targeting sequence and coding region polymorphisms of the manganese superoxide dismutase gene in German Parkinson disease patients. 1004 82

Hydroxyl radical (.OH) levels in blood, superoxide dismutase (SOD) activity in plasma (plasma-SOD) and in red blood cells (RBC) relative to Cu,Zn-SOD (SOD1) protein (RBC-SOD/SOD1), SOD1 protein in RBC (SOD1/RBC) and plasma (SOD1/plasma), and Mn-SOD protein in plasma (SOD2/plasma) were measured in patients with Parkinson's disease (PD), multiple-system atrophy (MSA) with parkinsonism, and in control subjects. Patients with PD had significantly higher.OH and plasma-SOD values and significantly lower RBC-SOD/SOD1 and SOD1/RBC values than the corresponding MSA and control values. In PD, RBC-SOD/SOD1 values were significantly lower in older patients and were negatively correlated with age.OH levels were significantly higher in PD patients with early onset, a long period of illness or severe Yahr stage, and were negatively correlated with onset and positively correlated with duration of illness. RBC-SOD/SOD1 values in PD patients who received pergolide therapy were significantly higher than those in PD patients who received neither pergolide nor bromocriptine therapy. Therefore, the higher.OH level and the lower SOD1 activity may play a role in the onset and progression of PD, and pergolide may act neuroprotectively by inducing SOD1 activity.
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PMID:Hydroxyl radical and superoxide dismutase in blood of patients with Parkinson's disease: relationship to clinical data. 1056 21

The effects of nigrostriatal pathway destruction on the mRNA levels of copper, zinc-dependent superoxide dismutase (Cu,Zn-SOD), manganese-dependent superoxide dismutase (Mn-SOD), and glutathione peroxidase in basal ganglia of adult rat were investigated using in situ hybridization histochemistry and oligodeoxynucleotide (single-stranded complementary DNA) probes. The 6-hydroxydopamine (6-OHDA)-induced destruction of the nigrostriatal pathway resulted in contralateral rotation to apomorphine and a marked loss of specific [(3)H]mazindol binding in the striatum (93%; P<0.05) and of tyrosine hydroxylase mRNA in substantia nigra pars compacta (SC) (93%; P<0.05) compared with control rats. Levels of Cu,Zn-SOD mRNA were decreased in the striatum, globus pallidus, and SC on the lesioned side of 6-OHDA-lesioned rats compared with sham-lesioned rats (P<0.05). Levels of Mn-SOD mRNA were increased in the nucleus accumbens (P<0.05), but decreased in the SC (P<0.05) on the lesioned side of 6-OHDA-treated rats compared with sham-lesioned rats. Lesioning with 6-OHDA had no effect on glutathione peroxidase mRNA levels in any region of basal ganglia examined. The significant changes in Cu,Zn-SOD and Mn-SOD mRNA indicate that SOD is primarily expressed by dopaminergic neurons of the nigrostriatal pathway, and that the Mn-SOD gene appears to be inducible in rat basal ganglia in response to both physical and chemical damage 5 weeks after 6-OHDA-lesioning. These findings may clarify the status of antioxidant enzymes, particularly Mn-SOD, in patients with Parkinson's disease and their relevance to disease pathogenesis.
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PMID:6-Hydroxydopamine-lesioning of the nigrostriatal pathway in rats alters basal ganglia mRNA for copper, zinc- and manganese-superoxide dismutase, but not glutathione peroxidase. 1173 Jul 1

The effect of He-Ne laser radiation on activity of MAO B, Cu/Zn-SOD, Mn-SOD, and catalase in blood cells from patients with Parkinson's disease was studied in vivo and in vitro. The effects of intravenous in vivo irradiation (intravenous laser therapy) were more pronounced than those observed in similar in vitro experiments. It is concluded that generalized effect of laser therapy involves interaction between blood cells.
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PMID:Laser modification of the blood in vitro and in vivo in patients with Parkinson's disease. 1291 Feb 78


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