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)

A number of neurological disorders including Alzheimer and Parkinson disease have been suggested to be caused by processes leading to lipid peroxidation. Other theories implicate the accumulation of damaged DNA, resulting from a defect in DNA repair, in the pathogenesis of these disorders. I suggest that these theories might be related, since the hydroxy free radical is known to attack DNA and inactivate enzymes so that oxygen metabolism has the potential to interfere with the maintenance of genomic integrity. Since psychometric intelligence correlates highly with erythrocyte glutathione peroxidase activity, a free radical scavenger, perhaps this might explain the marked intellectual impairment caused by chemotherapeutic agents such as cytosine arabinoside, as well as in Alzheimer disease.
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PMID:Dementia in cancer patients undergoing chemotherapy: implication of free radical injury and relevance to Alzheimer disease. 189 Sep 72

Two major lines of evidence support the hypothesis that an impairment of mitochondrial function may underlie neuronal death in Parkinson's disease. First, the neurotoxicity of the parkinsonism-inducing compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is due to the generation of its 1-methyl-4-phenylpyridinium (MPP+) metabolite in the central nervous system; the toxicity of MPP+ is likely to result from its ability to block mitochondrial electron flow at the level of complex I. Second, recent studies have revealed a deficiency of mitochondrial complex I activity in the brain as well as other tissues of parkinsonian patients. This enzyme activity reduction might be explained by a defect in one or more of the genes coding for the subunits of complex I. Since seven of these genes are localized in the mitochondrial genome, it is conceivable that abnormal mitochondrial DNA (mtDNA) might play a role in the pathogenesis of Parkinson's disease. The entire sequence of the human mitochondrial genome is known, and human mtDNA can be isolated and rapidly analyzed using techniques such as the polymerase chain reaction. Therefore, identification of an easily detectable mtDNA alteration might ultimately be used as a marker for the diagnosis and screening of Parkinson's disease.
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PMID:Mitochondrial DNA and Parkinson's disease. 190 41

Parkinson's disease has been associated with defects in oxidative phosphorylation (Oxphos). We analyzed mitochondria isolated from muscle biopsies of 6 patients with Parkinson's disease for deficiencies in Oxphos enzymes and for mutations in the mitochondrial DNA. Oxphos enzyme assays were compared to the 5 to 95% confidence intervals from 16 control subjects. Four patients had complex I defects, whereas 1 patient had a complex IV defect. A genetic basis for Parkinson's disease was suggested by the presence of affected relatives of 2 patients with Parkinson's disease. Known pathological mitochondrial DNA mutations (insertion-deletions or point mutations) were not found. We conclude that Parkinson's disease is a systemic disorder of Oxphos, probably of a complex genetic etiology. Premature cell death in the nigrostriatal dopamine pathway could be due to energetic impairment and accentuated free radical generation caused by an Oxphos defect.
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PMID:Mitochondrial oxidative phosphorylation defects in Parkinson's disease. 147 44

The reduced form of nicotinamide adenine dinucleotide coenzyme Q reductase (complex I) activity has recently been shown to be deficient in the substantia nigra of patients dying with Parkinson's disease. This biochemical defect is identical to that produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which also produces parkinsonism in humans. Complex I comprises 25 polypeptides, seven of which are encoded by mitochondrial DNA. Restriction fragment analysis of substantia nigra DNA from six patients with Parkinson's disease did not show any major deletion. In two cases, there were different novel polymorphisms that were not observed in control brain (n = 6) or blood (n = 34) samples.
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PMID:Mitochondrial DNA analysis in Parkinson's disease. 197 56

The total sequence data for mitochondrial DNA (mtDNA) revealed distinct clustering of point mutations (pms) in mtDNA among one patient with myoclonus epilepsy with ragged-red fibers (MERRF), two patients with Parkinson's disease (PD), two patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and one patient with fatal infantile cardiomyopathy (FICM). Among 33 to 62 pms found in each patients, sequentially diverged five clusters of pms were detected and designated as C-1 to C-5. C-1, consisted of fourteen pms, existed in the MERRF patient, C-1 and C-2 (nine pms) in one PD patient, C-1 to C-3 (seven pms) in another PD patient, C-1 to C-4 (one pm) in one MELAS patient and C-1 to C-5 (three pms) in another MELAS patient and the FICM patient. From these clustering of pms, a phylogenetic tree of mitochondrial encephalomyopathies (ME) was constructed. This tree clearly indicated that the ME and PD patients are members of the same gene family, and the MELAS and FICM patients are each others' closest relative. Each patient's unique pms (14 to 28 pms) were detected and, from their characteristic features, the types of the mutations specific for the disease were classified as mit- + syn- for MERRF, mit- + p- for PD, and syn- + mit- for MELAS. An inverse relation was found between the total number of pms and life span of the MELAS and FICM patients.
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PMID:Distinct clustering of point mutations in mitochondrial DNA among patients with mitochondrial encephalomyopathies and with Parkinson's disease. 202 3

Comparison of total mitochondrial DNA sequences of patients with idiopathic (deleted or hypertrophic) cardiomyopathy with those of patients with Parkinson's disease and mitochondrial encephalomyopathies revealed distinct clustering of point mutations among patients. Furthermore, an inverse relation was found between the total number of base-substitution and life span of the patients. Among point mutations found in each patient, sequentially diverged six clusters consisting of 14, 10, 7, 1, 2, and 3 mutations, respectively, were detected. Five sub-clusters consisting of 2, 2, 11, 1, and 1 mutations, respectively, were detected. From each cluster, the patient's unique mutations were diverged with three types of the mutations specific for the disease. The divergence allowed construction of a phylogenetic tree which clearly indicated that patients with idiopathic cardiomyopathy belong to the same mitochondrial DNA gene family of Parkinson's disease and mitochondrial encephalomyopathies.
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PMID:Patients with idiopathic cardiomyopathy belong to the same mitochondrial DNA gene family of Parkinson's disease and mitochondrial encephalomyopathy. 204 37

The mitochondrial genome codes for 13 proteins which are located in the respiratory chain. In postmortem brain of patients with Parkinson's disease, decreased activity of complex I of the respiratory chain could be demonstrated. Because seven subunits of complex I are coded by the mitochondrial genome, we analyzed the mitochondrial DNA of human postmortem substantia nigra, putamen, and frontal cortex by the Southern blot technique. No deletions of the mitochondrial genome could be demonstrated, thus indicating that either subunits which are encoded by the nuclear genome are decreased or enzyme activity is diminished by metabolites, toxins, or increase of Fe3+.
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PMID:Normal mitochondrial genome in brain from patients with Parkinson's disease and complex I defect. 212 Mar 89

Amantadine, a well-known antiviral agent, causing an increase in dopamine synthesis, release and the inhibition of re-uptake of noradrenaline and dopamine in central and peripheral catecholaminergic neurons, is successfully used in the treatment of Parkinson's disease. In the present paper, we have studied the effect of various doses of amantadine on in vivo prolactin secretion and the incorporation of 3H-thymidine and 3H-spiperone binding by the anterior pituitary gland of long-term diethylstilboestrol-treated male Wistar rats. Four weeks after a subcutaneous implantation of Silastic tubes containing 10 mg of diethylstilboestrol, a dramatic rise in serum prolactin levels was observed, accompanied by an increased uptake of 3H-thymidine by DNA anterior pituitary cells. Amantadine, given in the subcutaneous doses of 50, 5 and 0.5 mg/kg of body weight attenuated the stimulatory effect of stilboestrol on serum prolactin concentration in a dose-dependent fashion. On the other hand, the incorporation of 3H-thymidine into DNA pituitary cells in all the groups of amantadine-treated rats was only slightly suppressed. In an additional experiment, Scatchard analyses were performed on the in vitro 3H-spiperone binding kinetics in a dispersed anterior pituitary cell culture prepared from the pituitaries of 6-week diethylstilboestrol-treated rats. It has been found that amantadine injected in the dose of 5 mg/kg of body weight for 14 days induced a twofold decrease in the density of dopamine D2 binding sites (36.6 +/- 9.4 vs. 70.3 +/- 3.4 fmol/10(6) cells; p less than 0.02), while the apparent affinity of the receptors was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of amantadine on prolactin secretion, pituitary DNA synthesis and 3H-spiperone binding in male estrogen-treated rats. 214 19

Neurophysiological studies were performed on 8 patients with group A xeroderma pigmentosum during early childhood. EEG, ABR and NCV were normal during this period. In contrast, various sleep parameters detected by polysomnography showed abnormal findings even in the neurologically normal patient. Decreased % sleep REM was seen in a case, and decreased frequency of REMs were seen in another. Body movements were extremely high or low in frequency in 3 cases in whole night sleep. The distribution of body movements were abnormal; in control subjects, the frequency was higher in SREM and stage 1 than in slow wave sleep; in 7 cases, it was higher in slow wave sleep than in stage 1 or 2, or body movements were extremely frequent. Neurological examination revealed soft signs in various systems in early childhood. All cases except one showed hypotonia. Many cases were slow in learning to walk and the gait was unstable. Speech delay and decreased deep tendon reflexes, especially of patella, were seen in most cases. Since the neural deficits in XP may be related to the DNA repair defect, these findings indicate the possibility that some endogenous compounds distributing all over the nervous system might produce the DNA damages. Because the body movements during sleep are controlled by the nigrostriatal dopaminergic system, present data indicate that the basal ganglia might be one of the earliest degenerative systems in the CNS. Recently, some studies have suggested the possibility that oxygen radical mechanisms might be involved in the development of the dopamine neurodegenerative process in Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Neurophysiological studies on group A xeroderma pigmentosum in early childhood]. 217 31

Deleted mitochondrial DNA (mtDNA) was accumulated in the parkinsonian striatum, but the same deleted mtDNA was also detectable in the control striatum when cycles of polymerase chain reaction were increased. To discriminate between these pathological and physiological conditions, we quantitatively analyzed the proportion of deleted mtDNA to normal mtDNA by measuring the incorporation of alpha-[32P]deoxycytosine triphosphate into mtDNA fragments by using a laser image analyzer. To estimate the molar ratio of the deleted mtDNA to normal mtDNA, the radioactivity was normalized by each fragment size. By plotting logarithms of normalized radioactivities against PCR amplification cycles, straight lines were obtained with different slopes. By extrapolation of the line to the zero amplification, the proportion of mutant mtDNA to normal mtDNA in the original sample from the parkinsonian striatum was estimated to be ca. 5%, which was at least ten times higher than the proportion of ca. 0.3% in the control striatum. These results indicate that phenotype of the mutant mtDNA as Parkinson's disease is expressed when the proportion of deleted mtDNA to normal mtDNA exceeds a threshold of ten times higher value than in the normal subject.
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PMID:Quantitative determination of deleted mitochondrial DNA relative to normal DNA in parkinsonian striatum by a kinetic PCR analysis. 224 48


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