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)

Intracytoplasmic "colloid" inclusions have been described within neurons of several discrete central nervous system nuclei in a variety of entities. Although they lack specificity for any particular disease, they are believed to represent one of the morphologic changes of neuronal aging. Because premature aging of the substantia nigra has been one of the claimed mechanisms occurring in Parkinson's disease, the prevalence of colloid inclusions was studied within the substantia nigra in 15 patients with Parkinson's disease, 15 age-matched controls, 50 "normal" individuals, 10 patients with dementia of Alzheimer's type, and two patients with amyotrophic lateral sclerosis. Colloid bodies were found in the substantia nigra of all patients with Parkinson's disease and were virtually absent in the other populations. Histochemical and ultrastructural analyses showed that colloid bodies differ from early and mature Lewy bodies. They may represent the "pale" inclusions rarely mentioned in the literature and often mistaken for early Lewy bodies. "Colloid" bodies in the substantia nigra are diagnostic of Parkinson's disease. These findings support the theory of "premature" aging of the substantia nigra in this disease.
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PMID:Colloid (hyaline) inclusion bodies in the central nervous system: their presence in the substantia nigra is diagnostic of Parkinson's disease. 244 8

The striatum, in which the nigrostriatal dopaminergic neurons terminate, contains the highest amount of dopamine DA) in the brain. DA, released in the striatum, plays the rate limiting role in the control of motor functions by continuously inhibiting the release of acetylcholine (ACh) from the cholinergic interneurons of the caudate nucleus. DA content of the human caudate nucleus decreases by 13% per decade over the age of 45. Parkinson's disease seems to be a kind of selective, highly accelerated 'premature aging' of the nigrostriatal dopaminergic system, and the DA content of this neuron system shrinks within a short time to less than 10% of the normal level in the premorbid state. Clinical symptoms occur when the striatum loses more than 70% of its DA content. The chemical lesioning of the nigrostriatal dopaminergic neuron in the rat by 6-OH-dopamine (6-OHDA) leads to an increase of cholinergic activity in the striatum. The striatum taken from a rat pretreated with 6-OH dopamine is a useful experimental model for the rapid screening of compounds with potential therapeutic benefit in Parkinson's disease. A more specific neurotoxin than 6-OHDA is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which kills the cells in the substantia nigra with high specificity and induces rapidly parkinsonian-like condition in men and monkeys. (-)Deprenyl, the selective inhibitor of B-type MAO protects the striatum from the neurotoxic effects of 6-OHDA and MPTP. The amount of ACh released from the striatum of the rat increases from 372.8 +/- 31.4 to 746.5 +/- 44.0 pmol/g/min in 6-OHDA treated rats, it remains normal (371.1 +/- 34.7) if (-)deprenyl is given 30 minutes before 6-OHDA administration, hut is further increased (956.3 +/- 79.3 pmol/g/min), if clorgyline os injected 30 minutes before 6-OHDA. (-)Deprenyl prevents in a similar manner the neurotoxicity of MPTP in monkeys, whereas clorgyline, the selective inhibitor of MAO-A, is ineffective. The most important effect of deprenyl in the brain is the sensitization of dopaminergic neurons to physiological and pharmacological influences without eliciting an acute increase in dopaminergic activity. The effect of deprenyl is due, on the one hand, to the inhibition of MAO-B and, on the other hand, to inhibition of the uptake of dopamine.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Medicamentous strategy for improving the quality of life in the senescence]. 309 65

A total of 137 healthy participants aged from 20 to 79 years, including 59 over 60 years, were examined using a finger-tapping test. The test requested the participant to respond synchronously with the right middle finger to a periodic sound train with frequencies of 1, 2, 3, 4, and 5 Hz (cycles/sec). Difficulty keeping the rhythmic movement at a given rate was found to be a characteristic of aging. For the participants over 30 years, the mean rate of tapping deviated towards a faster rate for the stimulus frequency at 4 or 5 Hz (hastened tap, HT). The percentage of the participants who exhibited HT increased with decade of age; 0(20s), 11(30s), 13(40s), 17(50s), 30(60s) and 29(70s). HT in aging appears similar to hastened tapping which is typically observed in patients with Parkinson's disease and may be related to extrapyramidal dysfunction. Hastened tapping in the elderly supports the hypothesis that Parkinson's disease is a model for premature aging, suggesting that HT in aging represents an extrapyramidal motor dysfunction due to the neuroanatomical and neurochemical changes in the nigro-striatal system of the aging brain.
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PMID:Characteristic difficulty in rhythmic movement with aging and its relation to Parkinson's disease. 325 62

Oxidative stress and subsequent energy crisis have been proposed as the cause of nigral neuronal cell death in Parkinson's disease. We have reported defects in the mitochondrial respiratory chain and increased amount of deleted mitochondrial genome in the nigrostriatal system of patients with Parkinson's disease. Deletion in mitochondrial DNA could be ascribed to somatically acquired premature aging leading to cell death. To elucidate the contribution of maternally transmitted point mutations in mitochondrial DNA to the premature DNA damages, we employed a direct sequencing system and analyzed the total nucleotide sequences of mitochondrial DNA in the brains of five patients with idiopathic Parkinson's disease. There were no predominant point mutations among the patients in contrast to some neuromuscular diseases. However, each patient had several point mutations that would result in a significant change in the gene products. Some of these mutations may be involved either in the increased production of oxygen radicals from the mitochondrial respiratory chain or in the increased susceptibility of the respiratory chain components to oxidative damage. We propose that some of these mutations can be regarded as one of the risk factors accelerating degeneration of nigrostriatal pathway in Parkinson's disease.
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PMID:Point mutations of mitochondrial genome in Parkinson's disease. 772 27

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

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

Mitochondria have been hypothesized to play a role in both aging and neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease. Many studies have shown the accumulation of mitochondrial DNA (mtDNA) mutations in post-mitotic tissues and more recent data have shown this also to be a feature of aging mitotic tissues. Much of this data has been correlative, until recently with the development of polymerase gamma deficient mice which accumulate high levels of mtDNA mutations and show a premature aging phenotype, that a more causative role has been proposed. This article focuses on recent developments in aging research into the role that mtDNA mutations play in the aging process.
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PMID:Mitochondrial DNA mutations and aging. 1746 Jan 84

This is a mini-review of vitamin D(3), its active metabolites and their functioning in the central nervous system (CNS), especially in relation to nervous system pathologies and aging. The vitamin D(3) endocrine system consists of 3 active calcipherol hormones: calcidiol (25OHD(3)), 1alpha-calcitriol (1alpha,25(OH)2D(3)) and 24-calcitriol (24,25(OH)2D(3)). The impact of the calcipherol hormone system on aging, health and disease is discussed. Low serum calcidiol concentrations are associated with an increased risk of several chronic diseases including osteoporosis, cancer, diabetes, autoimmune disorders, hypertension, atherosclerosis and muscle weakness all of which can be considered aging-related diseases. The relationship of many of these diseases and aging-related changes in physiology show a U-shaped response curve to serum calcidiol concentrations. Clinical data suggest that vitamin D(3) insufficiency is associated with an increased risk of several CNS diseases, including multiple sclerosis, Alzheimer's and Parkinson's disease, seasonal affective disorder and schizophrenia. In line with this, recent animal and human studies suggest that vitamin D insufficiency is associated with abnormal development and functioning of the CNS. Overall, imbalances in the calcipherol system appear to cause abnormal function, including premature aging, of the CNS.
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PMID:Vitamin D, nervous system and aging. 1966 Aug 71

Mitochondria are major compartments in cells responsible for generating reactive oxygen species, which can cause the development of diabetes, Parkinson's disease and premature aging. Antioxidant systems in mitochondria are important for the prevention of diseases and reduction in the speed of aging. We investigated whether the reactive oxygen species generated in mitochondria induced the expression of metallothionein as an antioxidant. We compared the expression level of metallothionein mRNA in mitochondrial phospholipid hydroperoxide glutathione peroxidase (PHGPx)-overexpressed (PHGPx-ov) cells with that in control cells. These cells were treated with respiratory inhibitors, including rotenone and 2, 4-dinitrophenol; under these conditions, the PHGPx-ov cells were more resistant to cell death than the control cells. In addition, the intracellular reactive oxygen species level that was induced by these inhibitors was lower in PHGPx-ov cells than in control cells. This indicates that PHGPx degrades the membrane phospholipid hydroperoxide that is formed via the reactive oxygen species generated in mitochondria. The enhanced expression of metallothionein-I and metallothionein-II mRNA in rotenone-treated control cells was significantly decreased in rotenone-treated PHGPx-ov cells, suggesting that the hydrogen peroxide that is formed by superoxide anions generated in mitochondria diffuse into the cytosol and induce metallothionein mRNA expression. Conversely, the expression of manganese-superoxide dismutase (Mn-SOD) mRNA, which is localized in mitochondria, was not correlated with the intracellular reactive oxygen species level that was induced by rotenone treatment. These results suggest that metallothionein expression is sensitively and strictly regulated by the oxidative state that is induced by mitochondrial respiration.
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PMID:Enhanced metallothionein gene expression induced by mitochondrial oxidative stress is reduced in phospholipid hydroperoxide glutathione peroxidase-overexpressed cells. 1981 60

The accumulation of DNA damage has been widely implicated in premature aging and neurodegeneration. Progeroid syndromes with defects in the cellular response to DNA damage suggest that progressive genome instability represents an important aspect of the aging process. Moreover, most of the major neurodegenerative diseases are characterized by the accumulation of neuronal DNA damage, suggesting that impaired DNA repair mechanisms might be relevant to both premature aging and neurodegeneration. Two progeroid syndromes, Hutchinson-Gilford progeria syndrome and Werner's syndrome, are characterized by clinical features mimicking physiological aging at an early age and molecular studies have implicated decreased cell proliferation and altered DNA-damage responses as common causal mechanisms in the pathogenesis of both diseases. Defects in nucleotide excision repair cause three distinct human diseases: xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy; each of them is characterized by premature onset of pathologies that overlap with those associated with old age in humans. Increasing evidence also suggests that an impaired DNA repair, particularly the base excision repair pathway, might play a fundamental role in the development of age-related neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington' s disease. Here, we review the current knowledge on the role of DNA repair in premature aging and neurodegenerative diseases.
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PMID:DNA repair in premature aging disorders and neurodegeneration. 2029 65


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