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)

Accumulation of various mutations in the mitochondrial genome is proposed as an important contributor to aging and degenerative diseases. Extensive fragmentation of mtDNA was detected in association with increased 8-hydroxydeoxyguanosine content in the heart mitochondrial DNA (mtDNA) from a patient with premature aging and mitochondrial cardiomyopathy, who carried a mutation within the mitochondrial tRNA(Asp) gene. This result suggests that damage to mtDNA by hydroxyl radical and accumulation of deleted mtDNA can be accelerated by a specific mitochondrial genotype. Similarly, extensive fragmentation of mtDNA was also detected in cultured cells exposed to a high oxygen concentration atmosphere, implying that mtDNA is vulnerable to reactive oxygen species. To clarify the role of point mutations accumulated in mtDNA, we examined the sequence heterogeneity of mtDNA in the skeletal muscle of a MELAS patient who carried a mutation within the mitochondrial tRNA(leu)(UUR) gene. The analysis revealed that the frequency of mutant clones in the MELAS muscle was significantly higher than those in an age-matched control muscle and a control placenta. Some of these nucleotide substitutions were missense and nonsense mutations, which potentially have deleterious effects on the mitochondrial function. The frequency of nucleotide substitutions in the striatum of three patients with Parkinson's disease was also significantly higher than that in control tissues. We also observed increased protein modification by 4-hydroxy-2-nonenal, a lipid peroxidation by-product, in Parkinson's disease. These results suggests that a vicious cycle contributes to the progression of degenerative process. In this cycle, first a primary mitochondrial mutation(s) induces a mitochondrial respiratory defect, which increases the leakage of reactive oxygen species (ROS) from the respiratory chain. Then the ROS would trigger accumulation of secondary mtDNA mutations in postmitotic cells, leading to further aggravation of mitochondrial respiratory defects and increased production of ROS and lipid peroxides from mitochondria, and thus resulting in degeneration of cellular components.
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PMID:Accumulation of deletions and point mutations in mitochondrial genome in degenerative diseases. 868 11

A series of neurotoxic tetrahydroisoquinoline alkaloids has been detected in certain regions of mammalian brains. One such dopaminergic tetrahydroisoquinoline neurotoxin is salsolinol (SAL), which is suspected of being associated with the etiology of Parkinson's disease and neuropathology of chronic alcoholism. In the present study, we found that SAL in combination with Cu(II) induced strand scission in pBR322 and phiX174 supercoiled DNA, which was inhibited by the copper chelator, reactive oxygen species (ROS) scavengers, reduced glutathione, and catalase. SAL in the presence of Cu(II) caused hydroxylation of salicylic acid to produce 2,3- and 2,5-dihydroxybenzoic acids. Reaction of calf thymus DNA with SAL plus Cu(II) resulted in substantial oxidative DNA damage as determined by 8-hydroxydeoxyguanosine (8-OH-dG) formation. Blockade of the dihydroxy functional group of SAL abolished its capability to yield 8-OH-dG in the presence of Cu(II). The dehydro analog of SAL, 1-methyl-6,7-dihydroxy-3,4-dihydroisoquinoline, produced significantly high levels of 8-OH-dG when incubated with calf thymus DNA, even in the absence of Cu(II), which appears to be attributable to the tautomer formation by this compound. In another experiment, SAL exerted cytotoxicity when treated to rat pheochromocytoma (PC12) cells. Based on these findings, it seems likely that SAL undergoes redox cycling in the presence of Cu(II) with concomitant production of ROS, particularly hydroxyl radical, which could contribute to DNA damaging and cytotoxic properties of this neurotoxin.
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PMID:Oxidative DNA damage and cytotoxicity induced by copper-stimulated redox cycling of salsolinol, a neurotoxic tetrahydroisoquinoline alkaloid. 1139 Jan 86

8-hydroxy-2'-deoxyguanosine (8-OHdG) or 8-hydroxyguanosine (8-OHG), a product of oxidized DNA or RNA, is a good marker of oxidative cellular damage. In this study, we measured the 8-OHdG/8-OHG levels in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) and multiple system atrophy (MSA). Compared to age-matched controls, the mean levels of serum 8-OHdG/8-OHG were significantly higher in PD (P < 0.0001). Although no gender differences were observed in the controls, the mean values of serum 8-OHdG/8-OHG were significantly higher in female PD cases (P < 0.005) than in male patients. 8-OHdG/8-OHG levels in CSF were also increased significantly in patients with PD and MSA, however, their relative values were generally much lower than those in the serum. Together with previous studies showing increased peripheral 8-OHdG levels in Alzheimer's disease and amyotrophic lateral sclerosis, the data presented here suggest that systemic DNA/RNA oxidation is commonly observed in neurodegenerative diseases. Our results also imply that female patients with PD show higher levels of oxidative stress, which may explain the faster progression of this disease in females.
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PMID:Systemic increase of oxidative nucleic acid damage in Parkinson's disease and multiple system atrophy. 1189 75

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 mechanism of neurotoxicity produced by the interaction of melanin with manganese was investigated in PC12-derived neuronal cell cultures. The cells were incubated with melanin (25-500 microg/ml), MnCl2 (10 ng/ml-100 microg/ml) and a combination of both substances for 24 and 72 h. Incubation with either toxicant alone resulted in a minimal decrease in cell viability. The combination of melanin and manganese caused significant (up to 60%) decreases in viability of PC12 cells in a dose-dependent manner. Increases in oxidative DNA damage, indicated by levels of 8-hydroxy-2'deoxyguanosine (8-oxodG), was associated with decreased cell viability. Melanin alone, but not manganese alone, resulted in increased oxidative DNA damage. The maximal increase in 8-oxodG caused by melanin was about seven times higher than control after 24 h of exposure. The activity of the DNA repair enzyme, 8-oxoguanine DNA glycosylase (OGG1), was increased in cells incubated with single toxicants and their combinations for 24 h. On the third day of incubation with the toxicants, activity of OGG1 declined below control levels and cell viability significantly decreased. Melanin was observed to have an inhibitory effect on OGG1 activity. Study of the regulation of OGG1 activity in response to melanin and manganese may provide insights into the vulnerability of nigral neurons to oxidative stress in Parkinson's disease.
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PMID:Effects of melanin and manganese on DNA damage and repair in PC12-derived neurons. 1508 68

8-hydroxydeoxyguanosine (8-OHdG) has been used to evaluate oxidative stress. The authors investigated urinary 8-OHdG levels in 72 patients with Parkinson disease (PD) and in normal and disease control groups. The mean urinary 8-OHdG increased with the stage of PD and was not influenced by the current dose of DOPA. Our results suggest that urinary 8-OHdG is a potentially useful biomarker for evaluating the progression of PD.
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PMID:Urinary 8-hydroxydeoxyguanosine levels as a biomarker for progression of Parkinson disease. 1578 36

Glial heme oxygenase-1 is over-expressed in the CNS of subjects with Alzheimer disease (AD), Parkinson disease (PD) and multiple sclerosis (MS). Up-regulation of HO-1 in rat astroglia has been shown to facilitate iron sequestration by the mitochondrial compartment. To determine whether HO-1 induction promotes mitochondrial oxidative stress, assays for 8-epiPGF(2alpha) (ELISA), protein carbonyls (ELISA) and 8-OHdG (HPLC-EC) were used to quantify oxidative damage to lipids, proteins, and nucleic acids, respectively, in mitochondrial fractions and whole-cell compartments derived from cultured rat astroglia engineered to over-express human (h) HO-1 by transient transfection. Cell viability was assessed by trypan blue exclusion and the MTT assay, and cell proliferation was determined by [3H] thymidine incorporation and total cell counts. In rat astrocytes, hHO-1 over-expression (x 3 days) resulted in significant oxidative damage to mitochondrial lipids, proteins, and nucleic acids, partial growth arrest, and increased cell death. These effects were attenuated by incubation with 1 microM tin mesoporphyrin, a competitive HO inhibitor, or the iron chelator, deferoxamine. Up-regulation of HO-1 engenders oxidative mitochondrial injury in cultured rat astroglia. Heme-derived ferrous iron and carbon monoxide (CO) may mediate the oxidative modification of mitochondrial lipids, proteins and nucleic acids in these cells. Glial HO-1 hyperactivity may contribute to cellular oxidative stress, pathological iron deposition, and bioenergetic failure characteristic of degenerating and inflamed neural tissues and may constitute a rational target for therapeutic intervention in these conditions.
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PMID:Over-expression of heme oxygenase-1 promotes oxidative mitochondrial damage in rat astroglia. 1622 6

Parkinson's disease (PD) 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 has 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 (MT) against peroxynitrite-induced neurodegeneration in PD. 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 it enhanced the synthesis of 8-hydroxy-2-deoxyguanosine. Furthermore, it downregulated the expression of Bcl-2 and poly(adenosine diphosphate-ribose) polymerase, but upregulated 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 (DA) to dihydroxyphenylacetaldehyde (DopaL) was attenuated in metallothionein-transgenic fetal stem cells and in cells transfected with a mitochondrial genome, and was 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 downregulation of a mitochondrial genome and upregulation of caspase-3 as determined by reverse transcription polymerase chain reaction. These studies provide evidence that nitric oxide synthase activation and peroxynitrite ion overproduction may be involved in the etiopathogenesis of PD, and that metallothionein gene induction may provide neuroprotection.
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PMID:Peroxynitrite in the pathogenesis of Parkinson's disease and the neuroprotective role of metallothioneins. 1629 Dec 39

There is substantial evidence that a bioenergetic defect may play a role in the pathogenesis of Huntington's Disease (HD). A potential therapy for remediating defective energy metabolism is the mitochondrial cofactor, coenzyme Q10 (CoQ10). We have reported that CoQ10 is neuroprotective in the R6/2 transgenic mouse model of HD. Based upon the encouraging results of the CARE-HD trial and recent evidence that high-dose CoQ10 slows the progressive functional decline in Parkinson's disease, we performed a dose ranging study administering high levels of CoQ10 from two commercial sources in R6/2 mice to determine enhanced efficacy. High dose CoQ10 significantly extended survival in R6/2 mice, the degree of which was dose- and source-dependent. CoQ10 resulted in a marked improvement in motor performance and grip strength, with a reduction in weight loss, brain atrophy, and huntingtin inclusions in treated R6/2 mice. Brain levels of CoQ10 and CoQ9 were significantly lower in R6/2 mice, in comparison to wild type littermate control mice. Oral administration of CoQ10 elevated CoQ10 plasma levels and significantly increased brain levels of CoQ9, CoQ10, and ATP in R6/2 mice, while reducing 8-hydroxy-2-deoxyguanosine concentrations, a marker of oxidative damage. We demonstrate that high-dose administration of CoQ10 exerts a greater therapeutic benefit in a dose dependent manner in R6/2 mice than previously reported and suggest that clinical trials using high dose CoQ10 in HD patients are warranted.
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PMID:Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice. 1664 50

8-Hydroxy-2'-deoxyguanosine (8-OHdG), the predominant marker of oxidative DNA damage, may be a good biomarker for monitoring the progression of Parkinson's disease (PD). Unfortunately, there are no basic laboratory data examining 8-OHdG levels in animal models of PD. In this study, we demonstrate that rats lesioned with 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle display significantly elevated 8-OHdG levels in urine, serum, and substantia nigra, but not cerebrospinal fluid and striatum, compared to sham controls. These increments in 8-OHdG levels were detected at 2 days, but not at 7 days after the lesion suggesting that oxidative stress is restricted to the acute phase of 6-OHDA neurotoxicity. The present results support 8-OHdG as a biomarker that may aid both in the diagnosis and in the documentation of progression in PD.
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PMID:Increased 8-OHdG levels in the urine, serum, and substantia nigra of hemiparkinsonian rats. 1718 62


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