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)

Virtually any neurological disorder leads to activation of resident microglia and invasion of blood-borne macrophages, which are accompanied by an increase in number and change in phenotype of astrocytes, a phenomenon generally termed reactive astrocytosis. One of the functions attributed to activation of astrocytes is thought to involve restoration of tissue damage. Hitherto, the role of astrocytes in the inflammatory reaction occurring in Parkinson's disease has not received much attention. In the present study, we examined the inflammatory events in autopsies of the substantia nigra and putamen from Parkinson's disease patients using age-matched autopsies from normal patients as controls. In the substantia nigra, activation of microglia was consistently observed in all Parkinson's disease autopsies as verified from immunohistochemical detection of CR3/43 and ferritin. Activation of resident microglia was not observed in the putamen. No differences were observed between controls and Parkinson's disease autopsies from the substantia nigra and putamen, in terms of distribution, cellular density or cellular morphology of astrocytes stained for glial fibrillary acidic protein or metallothioneins I and II, the latter sharing high affinity for metal ions and known to be induced in reactive astrocytes, possibly to exert anti-oxidative effects. Together, these findings indicate that the inflammatory process in Parkinson's disease is characterized by activation of resident microglia without reactive astrocytosis, suggesting that the progressive loss of dopaminergic neurons in Parkinson's disease is an ongoing neurodegenerative process with a minimum of involvement of the surrounding nervous tissue. The absence of reactive astrocytosis in Parkinson's disease contrasts what follows in virtually any other neurological disorder and may indicate that the inflammatory process in Parkinson's disease is a unique phenomenon.
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PMID:The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson's disease. 1065 22

In Parkinson's Disease the neuromelanin in the substania nigra is known to contain considerably increased amounts of iron suggesting the presence of free, unprotected iron ions during its formation. Iron(II) is known to interact with peroxide via Fenton's reaction producing OH-radicals or ferryl (Fe(IV)) species. This can readily oxidize the neurotransmitter dopamine to the neurotoxic 6-hydroxydopamine (6-OHDA) which is a strong reducing agent. The produced 6-OHDA is, in turn, able to reduce and possibly release iron, as iron(II), from the iron storage protein ferritin. This cycle of events could well explain the development of Parkinson's Disease due to a continuous production of cell damaging species. The contrasting behaviour of 6-OHDA with some other important catecholamines is discussed.
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PMID:Redox reactions of neurotransmitters possibly involved in the progression of Parkinson's Disease. 1083 Aug 83

Iron may play an important role in the pathogenesis of Parkinson's disease (PD). Recent studies have shown that the iron-transporting glycoprotein lactoferrin (LF) and its receptor are increased in the substantia nigra (SN) in PD. We investigated whether plasma levels of LF are altered in dopa-responsive PD. Plasma LF was not different between patients with PD (n = 23; 306 +/- 116 [mean +/- standard deviation] ng/ml) and age- and sex-matched healthy control subjects (n = 15; 359 +/- 126 ng/ml ). However, LF was inversely correlated with PD severity (r = -0.68, P = 0.002), an association that remained significant after adjustment for treatment with levodopa, monoaminooxidase inhibitors, and dopa agonists (r = -0.53, P = 0.017). Plasma transferrin and ferritin levels were not different between groups and neither correlated with disease severity nor with LF levels. Together with the result of increased nigral lactoferrin, this finding is compatible with the hypothesis of an imbalance between LF levels in blood and SN in progressing PD. Larger and particularly longitudinal studies and measurements of LF in cerebrospinal fluid are warranted to further examine the role of LF in PD.
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PMID:Assessment of plasma lactoferrin in Parkinson's disease. 1121 73

A growing body of evidence has implicated oxidative stress as an important factor in the neuropathology associated with Parkinson's disease. Dopaminergic nigrostriatal neurons, the predominant cells lost in Parkinson's, are believed to be highly prone to oxidative damage due to the propensity for dopamine to auto-oxidize and thereby produce elevated levels of hydrogen peroxide and catecholamine quinones. Hydrogen peroxide formed during this process can either be converted by iron to form highly reactive hydroxyl radicals or removed through reduction by glutathione. Glutathione can also conjugate with quinones formed during dopamine oxidation preventing them from facilitating the release of iron from the iron-storage molecule ferritin. Alterations in both iron and glutathione levels in the substantia nigra have been correlated with the neuronal degeneration accompanying Parkinson's disease but a direct causative role for either has yet to be definitively proved. We will discuss the use of genetically engineered cell and mouse lines generated in our laboratory as models to examine the role that alterations in iron and glutathione levels may play in neurodegeneration of dopaminergic neurons of the substantia nigra associated with Parkinson's disease, and how these two parameters may interact with one another to bring this about.
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PMID:Do alterations in glutathione and iron levels contribute to pathology associated with Parkinson's disease? 1128 21

Iron homeostasis is tightly regulated, as cells work to conserve this essential but potentially toxic metal. The translation of many iron proteins is controlled by the binding of two cytoplasmic proteins, iron regulatory protein 1 and 2 (IRP1 and IRP2) to stem loop structures, known as iron-responsive elements (IREs), found in the untranslated regions of their mRNAs. In short, when iron is depleted, IRP1 or IRP2 bind IREs; this decreases the synthesis of proteins involved in iron storage and mitochondrial metabolism (e.g. ferritin and mitochondrial aconitase) and increases the synthesis of those involved in iron uptake (e.g. transferrin receptor). It is likely that more iron-containing proteins have IREs and that other IRPs may exist. One obvious place to search is in Complex I of the mitochondrial respiratory chain, which contains at least 6 iron-sulfur (Fe-S) subunits. Interestingly, in idiopathic Parkinson's disease, iron homeostasis is altered, and Complex I activity is diminished. These findings led us to investigate whether iron status affects the Fe-S subunits of Complex I. We found that the protein levels of the 75-kDa subunit of Complex I were modulated by levels of iron in the cell, whereas mRNA levels were minimally changed. Isolation of a clone of the 75-kDa Fe-S subunit with a more complete 5'-untranslated region sequence revealed a novel IRE-like stem loop sequence. RNA-protein gel shift assays demonstrated that a specific cytoplasmic protein bound the novel IRE and that the binding of the protein was affected by iron status. Western blot analysis and supershift assays showed that this cytosolic protein is neither IRP1 nor IRP2. In addition, ferritin IRE was able to compete for binding with this putative IRP. These results suggest that the 75-kDa Fe-S subunit of mitochondrial Complex I may be regulated by a novel IRE-IRP system.
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PMID:Regulation of the 75-kDa subunit of mitochondrial complex I by iron. 1131 46

We have identified five single nucleotide polymorphisms (SNPs) upstream (5') of the transferrin coding region. One polymorphism is in the 5' UTR at nt +49, and four are in the promoter region at nt -34, -551, -617, and -739, numbering from the start of transcription. The -34 and -617 SNPs are tightly but not completely linked. The -34 polymorphism lies between a conserved Sp1 site and the TATA box. The -617 polymorphism is within the DRII enhancer region. Five haplotypes have been defined from these SNPs by the identification of at least one homozygous individual, and two other haplotypes were deduced from heterozygous individuals. The total iron-binding capacity associated with each transferrin haplotype was haplotype 2 > 1 > 4 > 3. Transferrin promoter haplotype 2 had a significantly higher mean TIBC and haplotype 3 had a significantly lower mean TIBC than the more common haplotype 1. Persons with haplotype 4, which includes the -34T and -617A minor alleles, have a lower mean TIBC but the difference was not statistically significant. In normal individuals, the differences in the haplotypes were not found to be associated with differences in transferrin saturation and ferritin levels. There was no difference in the extent of increase in the mean TIBC levels in individuals with iron deficiency anemia in regard to their haplotype. Furthermore, there was no difference in the relative frequencies of the transferrin haplotypes in the iron-deficient population. In hemochromatosis patients who were homozygous for the C282Y HFE mutation, no particular haplotype was associated with a significant difference in transferrin saturation or ferritin levels. In White patients with Parkinson's disease, a disorder in which there is abnormal iron deposition in the brain, the presence of transferrin haplotype 3 was in slight excess over the normal White population.
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PMID:Polymorphisms in the transferrin 5' flanking region associated with differences in total iron binding capacity: possible implications in iron homeostasis. 1150 65

Free radicals and other so-called 'reactive species' are constantly produced in the brain in vivo. Some arise by 'accidents of chemistry', an example of which may be the leakage of electrons from the mitochondrial electron transport chain to generate superoxide radical (O2*-). Others are generated for useful purposes, such as the role of nitric oxide in neurotransmission and the production of O2*- by activated microglia. Because of its high ATP demand, the brain consumes O2 rapidly, and is thus susceptible to interference with mitochondrial function, which can in turn lead to increased O2*- formation. The brain contains multiple antioxidant defences, of which the mitochondrial manganese-containing superoxide dismutase and reduced glutathione seem especially important. Iron is a powerful promoter of free radical damage, able to catalyse generation of highly reactive hydroxyl, alkoxyl and peroxyl radicals from hydrogen peroxide and lipid peroxides, respectively. Although most iron in the brain is stored in ferritin, 'catalytic' iron is readily mobilised from injured brain tissue. Increased levels of oxidative damage to DNA, lipids and proteins have been detected by a range of assays in post-mortem tissues from patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, and at least some of these changes may occur early in disease progression. The accumulation and precipitation of proteins that occur in these diseases may be aggravated by oxidative damage, and may in turn cause more oxidative damage by interfering with the function of the proteasome. Indeed, it has been shown that proteasomal inhibition increases levels of oxidative damage not only to proteins but also to other biomolecules. Hence, there are many attempts to develop antioxidants that can cross the blood-brain barrier and decrease oxidative damage. Natural antioxidants such as vitamin E (tocopherol), carotenoids and flavonoids do not readily enter the brain in the adult, and the lazaroid antioxidant tirilazad (U-74006F) appears to localise in the blood-brain barrier. Other antioxidants under development include modified spin traps and low molecular mass scavengers of O2*-. One possible source of lead compounds is the use of traditional remedies claimed to improve brain function. Little is known about the impact of dietary antioxidants upon the development and progression of neurodegenerative diseases, especially Alzheimer's disease. Several agents already in therapeutic use might exert some of their effects by antioxidant action, including selegiline (deprenyl), apomorphine and nitecapone.
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PMID:Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. 1159 35

Dopaminergic neurones degenerate during Parkinson's disease and cell loss is most extensive in the subpopulation of melanized neurones located in the substantia nigra pars compacta. Iron accumulation, together with a lack of up-regulation of the iron-storing protein, ferritin, has been reported and may contribute to increased oxidative stress in this region. We investigated the binding activity of iron regulatory protein-1 (IRP1) to the iron-responsive element that precludes ferritin mRNA translation, in the substantia nigra of a group of parkinsonian patients who presented a statistically significant reduction in the number of nigral melanized-neurones and an increased iron content, together with unchanged H-ferritin and L-ferritin subunit levels as compared to matched controls. The levels of ferritin mRNAs and the binding activity of IRP1 to the iron-responsive element of ferritin mRNA did not differ significantly between the two groups. Moreover, there was no detectable contribution of the iron regulatory protein-2 (IRP2) binding activity. No change in IRP1 control of ferritin mRNA translation explains the lack of up-regulation of ferritin expression in cytoplasmic extracts of SNpc that would be normally expected with cytosolic iron accumulation. The data of this study do not favor changes in transcription and post-transcriptional regulation of ferritin expression in Parkinson's disease and suggest a 'compartmentalized' iron accumulation.
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PMID:Lack of up-regulation of ferritin is associated with sustained iron regulatory protein-1 binding activity in the substantia nigra of patients with Parkinson's disease. 1242 42

Several neurodegenerative disorders such as Parkinson's Disease (PD) and Alzheimer's Disease (AD) are associated with elevated brain iron accumulation relative to the amount of ferritin, the intracellular iron storage protein. The accumulation of more iron than can be adequately stored in ferritin creates an environment of oxidative stress. We developed a heavy chain (H) ferritin null mutant in an attempt to mimic the iron milieu of the brain in AD and PD. Animals homozygous for the mutation die in utero but the heterozygotes (+/-) are viable. We examined heterozygous and wild-type (wt) mice between 6 and 8 months of age. Macroscopically, the brains of +/- mice were well formed and did not differ from control brains. There was no evidence of histopathology in the brains of the heterozygous mice. Iron levels in the brain of the +/- and wild-type (+/+) mice were similar, but +/- mice had less than half the levels of H-ferritin. The other iron management proteins transferrin, transferrin receptor, light chain ferritin, Divalent Metal Transporter 1, ceruloplasmin, were increased in the +/- mice compared to +/+ mice. The relative amounts of these proteins in relation to the iron concentration are similar to that found in AD and PD. Thus, we hypothesized that the brains of the heterozygote mice should have an increase in indices of oxidative stress. In support of this hypothesis, there was a decrease in total superoxide dismutase (SOD) activity in the heterozygotes coupled with an increase in oxidatively modified proteins. In addition, apoptotic markers Bax and caspase-3 were detected in neurons of the +/- mice but not in the wt. Thus, we have developed a mouse model that mimics the protein profile for iron management seen in AD and PD that also shows evidence of oxidative stress. These results suggest that this mouse may be a model to determine the role of iron mismanagement in neurodegenerative disorders and for testing antioxidant therapeutic strategies.
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PMID:Mouse brains deficient in H-ferritin have normal iron concentration but a protein profile of iron deficiency and increased evidence of oxidative stress. 1247 13

Parkinson's disease (PD) is a progressive neurodegenerative disease with no known cure and affects approximately 1% of the elderly population. The major question in PD relates to the selective loss of dopaminergic neurons in patients. The underlying mechanism of genetic dysfunction and environmental toxins in contributing to the pathogenesis of PD may be oxidative stress. The interactions of genetic and environmental factors in PD may provide some answers to the longstanding question. In particular, the possibility that iron may provide selectivity to genetic susceptibility or dopamine reactivity in dopaminergic neuronal death is enhanced by the neuroprotection demonstrated in transgenic mice overexpressing ferritin or the use of iron chelators in MPTP-induced PD mouse. It will be important to dissect and understand the contributions of genes, environment and intrinsic cellular states in the generation and progression of the pathophysiology of PD.
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PMID:Interactions between environmental and genetic factors in the pathophysiology of Parkinson's disease. 1293 34


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