Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Work on the molecular mechanisms of MPTP neurotoxicity have inspired search into the function of mitochondria in idiopathic Parkinson's disease. All the studies show a decrease of 30 to 40% in the activity of the respiratory complex I in the mitochondria of the nigra substantia. This decreased activity is not found in other degenerative Parkinsonisms treated with L-Dopa and cannot be explained simply by age. It is not found in other tissues including muscles and platelets. The causal mechanism of this mitochondrial dysfunction is unknown but it is not related to a mutation in mitochondrial DNA.
 ...
PMID:[Idiopathic Parkinson disease and mitochondrial functions]. 767 50

Iron has recently been suggested to contribute to the pathogenesis of Parkinson's disease (PD) because of the finding of increased iron levels in the substantia nigra pars compacta (SNc) above those of control patients. Iron is capable of catalyzing numerous reactions which could lead to free radical formation and oxidative damage to DNA, proteins, lipid membranes, and other biological molecules. Neurodegeneration in the SNc of the PD brain may be a consequence of increased iron, which promotes these cytotoxic reactions. To test whether excess iron could play a causative role in the degeneration of nigral neurons, we infused 1.25-6.3 nmol of iron into the rat substantia nigra (SN) unilaterally utilizing two different infusion protocols. All infusates were isosmotic and pH-balanced in a citrate-bicarbonate vehicle. Animals were decapitated at either 1 or 2 months postinfusion. Striatal tissue was assayed for biogenic amines by HPLC and the remaining brainstem was processed for histological analysis. Iron-stained coronal sections revealed 1) no left/right staining difference with vehicle infusion, 2) a dose-dependent iron accumulation in the infused SN that was restricted to the zona compacta and dorsal-most zona reticularis when the lowest iron concentration was infused, and 3) a dose-dependent reduction in SN volume. Thionine-stained sections revealed neuronal loss and accompanying reactive gliosis within an area that corresponded closely to that of increased iron staining. These degenerative changes were more extensive in animals infused via a side-by side vs. a sequential protocol. Neurochemically, there was a highly significant correlation between the amount of iron infused intranigrally and magnitude of reductions in striatal DA, DOPAC, and HVA within the ipsilateral striatum. These data indicate that iron infusion into the SN can cause degenerative changes within the SN and that these changes can be restricted to the SNc region when low amounts of iron are infused. The data further support the hypothesis that iron-induced degeneration may contribute to the pathogenesis of PD.
 ...
PMID:Infusion of iron into the rat substantia nigra: nigral pathology and dose-dependent loss of striatal dopaminergic markers. 768 99

We have recently cloned the neurotensin receptor from human substantia nigra. Using in situ hybridization techniques, with an 35S-labeled antisense RNA probe complementary to this receptor complementary DNA, we studied the expression of the human neurotensin receptor in the brain from control and Parkinson's disease subjects. We also performed an analogous study with rat brain. Neurotensin receptor messenger RNA was present in high levels in melanized neurons of the substantia nigra pars compacta and the nucleus paranigralis (the ventral tegmental area for rat brain). Background levels of signals for neurotensin receptor messenger RNA were detected in the nucleus ruber, the colliculus inferior and the striatal subdivisions (the nucleus caudatus, the putamen and the nucleus accumbens) of both human and rat brain. All these areas, except the nucleus ruber and the collicus inferior, contain very high to high levels of neurotensin receptor binding sites. Additionally, Parkinson's disease brains had markedly fewer melanized (possibly dopaminergic) neurons, as expected, and correspondingly very low or background levels of messenger RNA for neurotensin receptor. We have also demonstrated heterogeneity among the melanized cells expressing messenger RNA encoding the neurotensin receptor in the substantia nigra and the nucleus paranigralis of human brain. The neurons in the nucleus paranigralis had lower melanin pigmentation and higher expression of neurotensin receptor messenger RNA. In general, the expression of the messenger RNA within the highly and evenly melanized neurons was lower than that found in low or unevenly pigmented neurons. The neurons in the nucleus paranigralis had lower melanin pigmentation and higher expression of neurotensin receptor messenger RNA. The low pigmented neurons in the ventral tier of the substantia nigra had relatively high expression. On the other hand, highly and evenly melanized neurons in these regions of the brain had low expression of neurotensin receptor messenger RNA. Together with the previous binding data, it is suggested that not only in rat brain, but also in human brain, melanized (possibly dopaminergic) neurons in the substantia nigra and the nucleus paranigralis (ventral tegmental area of rat brain) synthesize neurotensin receptors and express them in their perikarya and the terminal regions. Additionally, the heterogeneity of the melanized neurons in human brain may play a role in the normal function of dopaminergic systems and probably in the etiology of some neurological and psychiatric disorders.
 ...
PMID:Heterogeneity of melanized neurons expressing neurotensin receptor messenger RNA in the substantia nigra and the nucleus paranigralis of control and Parkinson's disease brain. 770 May 29

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.
 ...
PMID:Point mutations of mitochondrial genome in Parkinson's disease. 772 27

The hypothesis that L-DOPA therapy in Parkinson's disease may augment neuronal damage and thus accelerate the progression of the disease remains controversial. In this study, we demonstrate that L-DOPA induces death of catecholaminergic cells in vitro via an active program of apoptosis. Treatment of PC12 cells with clinically applicable concentrations of L-DOPA (25-100 microM) induced cell death via a mechanism which exhibited morphological and biochemical characteristics of apoptosis, including chromatin condensation, membrane blebbing, and internucleosomal DNA fragmentation. L-DOPA-induced apoptosis was cell and drug-type specific. Toxicity is an intrinsic property of the drug molecule since it was not suppressed by inhibiting conversion of L-DOPA to dopamine. However, L-DOPA toxicity was inhibited by antioxidants, suggesting that activation of apoptosis is mediated by oxygen radicals. Our finding that L-DOPA-induced cell death in vitro occurs via apoptosis explains the lack of evidence supporting its toxicity in vivo, since apoptotic neurons are rapidly phagocytosed in vivo without causing damage to surrounding tissue. Furthermore, since apoptosis is an active cellular program which can be modulated, we suggest clinical approaches for decreasing L-DOPA toxicity, thus preventing acceleration of neuronal damage in Parkinson's disease.
 ...
PMID:Induction of apoptosis in catecholaminergic PC12 cells by L-DOPA. Implications for the treatment of Parkinson's disease. 776 91

Decreased mitochondrial Complex I activities and a 4,977-bp deletion in mitochondrial DNA (mtDNA) have been reported in patients with Parkinson's disease. Based on the assumption of possible links between this 4,977-bp deletion and the etiology of Parkinson's disease, we analyzed mtDNA of blood cells from 15 patients with young-onset Parkinson's disease after the DNA was amplified by polymerase chain reaction. We could not detect the 4,977-bp mtDNA deletion in any of these patients. This result suggests that Parkinson's disease is not a mitochondrial disease due to the 4,977-bp mtDNA deletion. The 4,977-bp deletion in mtDNA appears to be an age-related phenomenon.
 ...
PMID:Absence of 4,977-bp deletion of blood cell mitochondrial DNA in patients with young-onset Parkinson's disease. 778 27

In recent years much has been speculated about a pathogenic role of mitochondrial defects in Parkinson's disease. Ozawa et al. (BBRC 176, 938-946, 1991) have described an A/T transversion at nucleotide 7237 of mitochondrial DNA affecting cytochrome-c-oxidase (complex IV) of the respiratory chain that could contribute to the pathogenesis of PD. Employing PCR based genomic sequencing and restriction enzyme analysis on 19 cases of Lewy-body parkinsonism, we exclude this mutation as a common cause of Parkinson's disease. This demonstrates the need for systematic sequencing of the mitochondrial genome in a large number of histologically verified cases of Parkinson's disease.
 ...
PMID:Absence of the mitochondrial A7237T mutation in Parkinson's disease. 779 85

Adeno-associated viral (AAV) vectors are non-pathogenic, integrating DNA vectors in which all viral genes are removed and helper virus is completely eliminated. To evaluate this system in the post-mitotic cells of the brain, we found that an AAV vector containing the lacZ gene (AAVlac) resulted in expression of beta-galactosidase up to three months post-injection in vivo. A second vector expressing human tyrosine hydroxylase (AAVth) was injected into the denervated striatum of unilateral 6-hydroxydopamine-lesioned rats. Tyrosine hydroxylase (TH) immunoreactivity was detectable in striatal neurons and glia for up to four months and we also found significant behavioural recovery in lesioned rats treated with AAVth versus AAVlac controls. Safe and stable TH gene transfer into the denervated striatum may have potential for the genetic therapy of Parkinson's disease.
 ...
PMID:Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. 784 13

The mechanisms that lead ultimately to neuronal death in pathological ageing of the brain remain mostly unknown as in the case of Parkinson's disease where there is a progressive and selective loss of dopaminergic neurons within the substantia nigra. Dopamine-expressing PC12 cells that were neuronally differentiated by nerve growth factor treatment were chosen as a culture model in which to study some of the changes that may occur during the course of the degenerative process. They were exposed to the calcium ionophore A23187 in order to produce a sustained rise in cytoplasmic calcium, a phenomenon related to various pathological conditions. The degenerative effects of the ionophore were dose- and time-dependent. They were characterized by early fragmentation of the neurites followed ultimately by a loss in cell viability. Biochemical changes, such as a decrease in [3H]dopamine uptake and modulations of the tyrosine hydroxylase gene, were detected before macroscopic evidence of cell suffering (e.g. neurite fragmentation) could be observed. Although an ongoing degenerative process was occurring in cell somata, PC12 cells were able to recover upon ionophore withdrawal. Characteristics of apoptosis such as chromatin condensation and DNA fragmentation were detectable in a small population of dying cells. DNA fragmentation could be prevented by the endonuclease inhibitor aurintricarboxylic acid. New protein synthesis was not required, as cycloheximide failed to prevent degeneration. Taken together, these results suggest that differentiated PC12 cells react to calcium stress through a sequence of regulatory processes which appears to be independent of the apoptotic pathway.
 ...
PMID:Morphological and molecular characterization of the response of differentiated PC12 cells to calcium stress. 791 84

A major theory regarding the mechanism of neuronal degeneration in several movement disorders is that mitochondrial defects may play a role. Biochemical studies in Parkinson's disease, Huntington's disease, multiple system atrophy, and idiopathic dystonia have shown defects in enzymes of oxidative phosphorylation in postmortem brain tissue, platelets, muscle, or lymphocytes. The basal ganglia and substantia nigra are also particularly susceptible to the accumulation of age-dependent mitochondrial DNA deletions, which may contribute to the delayed onset of movement disorders. The 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine model of Parkinson's disease involves conversion to 1-methyl-4-phenylpyridinium, which then inhibits complex I of the electron transport chain. Our studies show that the complex II inhibitor 3-nitropropionic acid can closely replicate the neurochemical, histologic, and clinical features of Huntington's disease. The mechanism of neuronal death in both these models may be slow excitotoxicity. Both direct biochemical studies and animal models of movement disorders therefore suggest that mitochondrial dysfunction may play a direct role in their pathogenesis.
 ...
PMID:Mitochondrial dysfunction in movement disorders. 795 42


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>