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 DNA damage can cause mutation and cell death. We show that L-DOPA, dopamine and 3-O-methyl-DOPA cause extensive oxidative DNA damage in the presence of H2O2 and traces of copper ions. 8-Hydroxyguanine is the major product. Iron ions were much less effective and manganese ions did not catalyse DNA damage. We propose that copper ion release, in the presence of L-DOPA and its metabolites, may be an important mechanism of neurotoxicity, e.g. in Parkinson's disease and amyotrophic lateral sclerosis.
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PMID:Intense oxidative DNA damage promoted by L-dopa and its metabolites. Implications for neurodegenerative disease. 795 67

We report that exposure of cultured, postmitotic chick-embryo sympathetic neurons, to physiological concentrations of dopamine (0.1-1 mM) for 24 h initiates a cellular death process characteristic of apoptosis (= programmed-cell-death, PCD). Dopamine caused marked morphological alterations, mainly axonal disintegration and severe shrinkage and condensation of cell bodies. Flow-cytometric analysis of propidium-iodide-stained cell nuclei revealed the characteristic apoptotic nuclear fragmentation: increase in nuclear granularity and emergence of a large, distinct population of nuclei with reduced DNA content (subdiploid, apoptotic peak). These alterations were similar to changes induced by nerve growth factor (NGF) deprivation, a model of sympathetic neuronal PCD. Alterations were inhibited by the anti-oxidative agent DTT. Inappropriate, dopamine-induced activation of PCD might have a role in nigral neuronal degeneration in Parkinson's disease.
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PMID:Dopamine induces apoptosis-like cell death in cultured chick sympathetic neurons--a possible novel pathogenetic mechanism in Parkinson's disease. 804 91

A variety of degenerative diseases involving deficiencies in mitochondrial bioenergetics have been associated with mitochondrial DNA (mtDNA) mutations. Maternally inherited mtDNA nucleotide substitutions range from neutral polymorphisms to lethal mutations. Neutral polymorphisms are ancient, having accumulated along mtDNA lineages, and thus correlate with ethnic and geographic origin. Mildly deleterious base substitutions have also occurred along mtDNA lineages and have been associated with familial deafness and some cases of Alzheimer's Disease and Parkinson's Disease. Moderately deleterious nucleotide substitutions are more recent and cause maternally-inherited diseases such as Leber's Hereditary Optic Neuropathy (LHON) and Myoclonic Epilepsy and Ragged-Red Fiber Disease (MERRF). Severe nucleotide substitutions are generally new mutations that cause pediatric diseases such as Leigh's Syndrome and dystonia. MtDNA rearrangements also cause a variety of phenotypes. The milder rearrangements generally involve duplications and can cause maternally-inherited adult-onset diabetes and deafness. More severe rearrangements frequently involving detections have been associated with adult-onset Chronic Progressive External Ophthalmoplegia (CPEO) and Kearns-Sayre Syndrome (KSS) or the lethal childhood disorder, Pearson's Marrow/Pancreas Syndrome. Defects in nuclear-cytoplasmic interaction have also been observed, and include an autosomal dominant mutation causing multiple muscle mtDNA deletions and a genetically complex disease resulting in the tissue depletion of mtDNAs. MtDNA nucleotide substitution and rearrangement mutations also accumulate with age in quiescent tissues. These somatic mutations appear to degrade cellular bioenergetic capacity, exacerbate inherited mitochondrial defects and contribute to tissue senescence. Thus, bioenergetic defects resulting from mtDNA mutations may be a common cause of human degenerative disease.
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PMID:Mitochondrial DNA mutations in diseases of energy metabolism. 807 79

Mitochondrial DNA (mtDNA) variants associated with Alzheimer disease (AD) and Parkinson disease (PD) were sought by restriction endonuclease analysis in a cohort of 71 late-onset Caucasian patients. A tRNA(Gln) gene variant at nucleotide pair (np) 4336 that altered a moderately conserved nucleotide was present in 9/173 (5.2%) of the patients surveyed but in only 0.7% of the general Caucasian controls. One of these patients harbored an additional novel 12S rRNA 5-nucleotide insertion at np 956-965, while a second had a missense variant at np 3397 that converted a highly conserved methionine to a valine. This latter mutation was also found in an independent AD + PD patient, as was a heteroplasmic 16S rRNA variant at np 3196. Additional studies will be required to determine the significance, if any, of these mutations.
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PMID:Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients. 810 67

Treatment with selegiline produced profound hypoglycemia in a 70-year-old man with Parkinson's disease. The hypoglycemia was accompanied by hyperinsulinemia and persisted for 1 week after selegiline was discontinued. Although this side effect of antidepressant monoamine oxidase inhibitors was well documented in 1959-1968 publications, it was not known to the manufacturer of selegiline. Effects of drugs on glucose metabolism may be predictable through a novel molecular modeling technique developed in our laboratories, which shows that glucose exhibits stereochemical complementarity to a specific site in partially unwound DNA. Selegiline and other molecules affecting glucose metabolism fit into the same DNA base sequence. It therefore should be possible to employ this technique to identify pharmaceutical agents that possess hypoglycemic or hyperglycemic effects in vivo.
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PMID:Hypoglycemia caused by selegiline, an antiparkinsonian drug: can such side effects be predicted? 813 55

The role of heredity in Parkinson's disease (PD) is controversial. We report a pair of monozygotic twins (confirmed by DNA fingerprints) concordant for PD. Their disease began when they were 62 and 63 years old. Both patients presented with left-side bradykinesia. One of the twins had a long history of depression. Both patients had typical manifestations of PD, which were responsive to dopaminergic therapy. The similar age of onset along with the similar clinical characteristics of these twins suggests that hereditary or genetic susceptibility may be important in the etiology of PD.
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PMID:Identical twins with similar onset of Parkinson's disease: a case report. 817 May 61

This paper proposes a prenatal seasonal hypopigmentation influence associated with anomalous cerebral dominance that occurs during the winter or early spring. A possible mechanism would be seasonal changes in sex hormone levels that affect the activation and inactivation of DNA by reversible methylation. The proposed prenatal seasonal hypopigmentation effect might be relevant to dyslexia, Prader-Willi syndrome, breast cancer, Alzheimer's and Parkinson's disease. Putative chromosomal loci associated with the proposed seasonal mechanism would be 15q11-13 (dyslexia and Prader-Willi syndrome), 21q region (breast cancer and Alzheimer's disease) and 19p region (pigmentation gene).
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PMID:Hypopigmentation, anomalous cerebral dominance and seasonality. 818 25

Different abnormalities in mitochondrial electron transport chain activity have been demonstrated in muscle and other tissues of patients with idiopathic Parkinson's disease (PD). We studied eight Spanish patients with PD to evaluate the functional activity of the electron transport chain in muscle mitochondria from patients of this country. We found lower complex I activity (nmol.min-1.mg-1) in patients (245.8 +/- 42.8) than in controls (331.6 +/- 60.1) (p = 0.004) and lower complex IV activity in patients (46.1 +/- 9) than in controls (144.1 +/- 42.3) (p = 0.00001). Complex V activity was also decreased in two patients and complex II and III activities were normal in all of them. Although these results strongly suggest an alteration in mitochondrial DNA in PD, the various electron transport chain defects in different tissues seem to be nonspecific.
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PMID:Mitochondrial respiratory chain activity in skeletal muscle from patients with Parkinson's disease. 823 23

There are several reports of a defect of complex I in the substantia nigra (SN) of Parkinson's disease (PD) patients. To evaluate whether this is specific to dopaminergic neurons or the phenotypically relevant consequence of a widespread failure of the mitochondrial oxidative phosphorylation (OXPHOS) system, we measured respiratory enzyme activities in muscle homogenates from 16 PD patients and eight age-matched controls, and in muscle isolated mitochondria of six PD patients and six age-matched controls. We found no difference between the PD and control groups. In addition, we detected, by polymerase chain reaction, the mitochondrial DNA (mtDNA) "common deletion" (CD) in muscle specimens of 14 of 17 PD patients, but we obtained similar results in age-matched controls. In both groups, the amount of CD-specific deleted (delta) mtDNA ranged from 0.0% to 0.1%. Our data suggest that PD cannot be attributed to a multisystem decline of mitochondrial OXPHOS, and that lesions of muscle mtDNA in PD are likely due to normal aging. However, there was a remarkable accumulation of delta mtDNA in the SN of a PD patient and an age-matched control, suggesting that the SN is exquisitely sensitive to age-dependent damage of the mitochondrial genome.
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PMID:Respiratory chain and mitochondrial DNA in muscle and brain in Parkinson's disease patients. 823 23

The copper-zinc-dependent superoxide dismutase messenger RNA expression was studied at cellular level by in situ hybridization, using a 35S-labelled complementary DNA probe homologous to human copper-zinc-dependent superoxide dismutase messenger RNA, in the dopaminergic neuron-containing areas of the human mesencephalon (the substantia nigra pars compacta, ventral tegmental area, central gray substance and peri- and retrorubral region corresponding to catecholaminergic cell group A8). The autoradiographic labelling signal was localized in neurons. No detectable hybridization signal could be found in the glial cells. Copper-zinc-dependent superoxide dismutase messenger RNA was detected in melanin-containing neurons as well as in non-melanized neurons. Quantification at cellular level, taking the autoradiographic silver grain density as an index of the abundance of copper-zinc-dependent superoxide dismutase messenger RNA, indicated that hybridization level was higher in the melanized than in the non-melanized neurons within a region. Among melanized neurons, cellular copper-zinc-dependent superoxide dismutase messenger RNA content was lowest in the neurons of the substantia nigra. No significant difference in levels of transcripts was evidenced between the groups of non-melanized neurons. The data suggest that the abundance of copper-zinc-dependent superoxide dismutase messenger RNA is higher in the mesencephalic neurons containing neuromelanin compared to other neurons. Thus, the melanized neurons have a particular defence system against oxygen toxicity, which may represent a basis for their preferential vulnerability to Parkinson's disease.
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PMID:Preferential expression of superoxide dismutase messenger RNA in melanized neurons in human mesencephalon. 835 Sep 85


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