Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The diagnosis of Parkinson's disease is based on clinical features with pathological verification. However, autopsy has been found to confirm a specialist diagnosis in only about 75% of cases. Especially early in the course of the disease, the clinical diagnosis can be difficult. Imaging of presynaptic dopamine transporters (DAT receptors) has provided a possible diagnostic probe in the evaluation of Parkinson's disease. The cocaine analogue [(123)I]-2-beta-carboxymethoxy-3-beta(4-iodophenyl)tropane ([(123)I]-beta-CIT) is one of several radioligands that have been developed for single-photon emission tomography (SPET). The purpose of this study was to evaluate the impact of [(123)I]-beta-CIT SPET on the diagnosis and clinical management of patients with a primary, tentative diagnosis of parkinsonism. We undertook a retrospective evaluation of the clinical records of 90 consecutive patients referred to [(123)I]-beta-CIT SPET from the neurological department, Bispebjerg Hospital. In 58 subjects the scans revealed altered tracer uptake consistent with Parkinson's disease, progressive supranuclear palsy and multiple system atrophy. A significant change in the management or treatment because of the scan was found in 25 patients (28%). The sensitivity of the examination was 97% and the specificity 83%. In conclusion, a significant clinical impact of DAT receptor SPET imaging was found. DAT receptor imaging is a useful diagnostic probe in patients with a possible diagnosis of parkinsonism.
Eur J Nucl Med Mol Imaging 2002 Dec
PMID:Clinical impact of diagnostic SPET investigations with a dopamine re-uptake ligand. 1245 97

Tau is a microtubule-associated protein involved in microtubule assembly and stabilization. Abnormal filamentous tau deposits constitute a major defining characteristic of several neurodegenerative diseases, including Alzheimer's disease. Although the presence of tau pathology correlates with the symptoms of Alzheimer's disease, there was no genetic evidence linking tau to neurodegeneration until recently. However, since 1998, the identification of more than 25 mutations in the tau gene, associated with frontotemporal dementia and parkinsonism linked to chromosome 17, has demonstrated that tau dysfunction can lead to neurodegeneration and the development of clinical symptoms.
Trends Mol Med 2002 Dec
PMID:Tau gene mutations: dissecting the pathogenesis of FTDP-17. 1247 Sep 88

Regulation of dopamine D2 receptor (D2) function plays an important role in alleviating either the motor deficits of Parkinson's disease or psychotic symptoms of schizophrenia. D2 also plays a critical role in sensorimotor gating which can be measured by monitoring the prepulse inhibition of the startle response. Alternative splicing of the D2 gene generates two isoforms, D2S and D2L. Here we investigated the role of D2S and D2L in the mechanisms of action of dopaminergic drugs, using mice lacking D2L (D2L(-/-)) but expressing D2S as a model system. We found that the typical antipsychotic raclopride was much less potent in inhibiting locomotor activity and eliciting catalepsy (or parkinsonism) in D2L(-/-) mice, whereas the atypical antipsychotic clozapine was equally effective in D2L(-/-) and wild-type mice. These suggest that the deletion of D2L diminishes drug-induced parkinsonism. Furthermore, two dopamine agonists, amphetamine and apomorphine, reduced prepulse inhibition to a similar degree in D2L(-/-) and wild-type mice. These results together suggest that D2S alone can mediate the action of clozapine and the dopamine agonist-induced disruption of prepulse inhibition. The differential binding affinities of these agents for D2S vs D2L were not sufficient to explain the divergent effects of typical vs atypical antipsychotics in D2L(-/-) mice. These findings suggest that D2S and D2L may differentially contribute to the therapeutic actions and side effects of antipsychotic agents, and may have implications for developing better antipsychotic agents.
Mol Psychiatry 2002
PMID:Dopamine D2S and D2L receptors may differentially contribute to the actions of antipsychotic and psychotic agents in mice. 1247 22

Betz cells are giant motoneurons located in layer Vb of the primate primary motor cortex. We conducted stereological analyses of Betz cells and neighboring pyramidal cells from the brains of six neurologically normal elderly humans to determine their volume, total number, and spatial distribution, and to relate these data to functional localization. The distribution of cellular volumes exhibits a bimodal pattern, delineating two different subpopulations. Betz cell volumes follow a mediolateral gradient, the largest Betz cells being located on the most medial part of the motor cortex. Additionally, the shape of Betz cells varies between the rostral and caudal parts of the primary motor cortex, supporting the notion that there are anatomically distinct zones in primary motor cortex. The total number of Betz cells per hemisphere accounts for about one-tenth of the total number of pyramidal cells in layer Vb. Analysis of spatial distribution using Voronoi tessellation revealed maximal clustering of Betz cells in a zone situated two-thirds from the midline along the mediolateral axis of the primary motor cortex. These data suggest that Betz cells have a discrete subregional distribution that may correspond to certain aspects of the functional parcellation of area 4. These results may offer a histological correlate of functional imaging studies and are relevant in the context of neurodegenerative diseases such as amyotrophic lateral sclerosis, progressive supranuclear palsy, and Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia, and in studies of normal brain aging.
Anat Rec A Discov Mol Cell Evol Biol 2003 Feb
PMID:Stereologic characterization and spatial distribution patterns of Betz cells in the human primary motor cortex. 1252 89

Mutations of the parkin gene on chromosome 6q25-27 are the predominant genetic cause of early-onset and autosomal recessive juvenile parkinsonism. Parkin is a multi-domain protein with ubiquitin-protein E3 ligase activity that has a role in the proteasome-mediated degradation of target substrates. Although the parkin gene contains an expanded intron/exon structure and spans more than 1.3 Mb, we have identified a novel transcript that initiates 204 bp upstream of parkin and spans over 0.6 Mb, antisense to parkin. We have tentatively named this novel gene Parkin co-regulated gene, or PACRG. A 35 bp site of bi-directional transcription activation within the common promoter was mapped using dual-luciferase assays. This region appeared to be responsible for the majority of transcription regulation of both genes, and comparison of the mouse and human sequences revealed conserved transcription factor-binding sites. A 15 bp interval within the activation region, containing a non-canonical myc-binding site, bound nuclear protein derived from human substantia nigra. Database analysis identified highly conserved homologs of PACRG encoded by the mouse and Drosophila genomes, and Northern analysis demonstrated that PACRG and parkin were co-expressed in many tissues, including brain, heart and muscle. Western analysis revealed a protein of the predicted size, approximately 30 kDa, which was expressed in mouse and human brain. Although PACRG protein lacks known functional domains, in silico prediction suggests a potential link to the ubiquitin/proteasome system.
J Mol Biol 2003 Feb 07
PMID:Identification of a novel gene linked to parkin via a bi-directional promoter. 1254 87

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that induces Parkinsonism in humans, monkeys, and mice and oxidative stress in mammalian cells and tissues. In the present study, the relationship between the generation of lipid peroxidation products and DNA damage was studied in mice treated with MPTP. The frequency of micronucleated polychromatic erythrocytes (MN-PCE) and the concentrations of malonaldehyde and 4-hydroxyalkenals were determined in the bone marrow and peripheral blood of mice 0, 24, 48, 72, and 96 hr after treatment with MPTP, cyclophosphamide as a positive control, or diluent. Both MN-PCE and the lipid peroxidation products increased in MPTP-treated mice, with significant levels being detected in bone marrow starting at 24 hr after treatment and in blood starting at 48 hr after treatment. These results suggest that the generation of oxidative products is related to the DNA damage produced by MPTP in mice.
Environ Mol Mutagen 2003
PMID:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced lipid peroxidation and DNA damage in mouse bone marrow and blood. 1255 93

Parkin gene mutations have been implicated in autosomal-recessive early-onset parkinsonism and lead to specific degeneration of dopaminergic neurons in midbrain. To investigate the role of Parkin in neuronal cell death, we overproduced this protein in PC12 cells in an inducible manner. In this cell line, neuronally differentiated by nerve growth factor, Parkin overproduction protected against cell death mediated by ceramide, but not by a variety of other cell death inducers (H(2)O(2), 4-hydroxynonenal, rotenone, 6-OHDA, tunicamycin, 2-mercaptoethanol and staurosporine). Protection was abrogated by the proteasome inhibitor epoxomicin and disease-causing variants, indicating that it was mediated by the E3 ubiquitin ligase activity of Parkin. Interestingly, Parkin acted by delaying mitochondrial swelling and subsequent cytochrome c release and caspase-3 activation observed in ceramide-mediated cell death. Subcellular fractionation demonstrated enrichment of Parkin in the mitochondrial fraction and its association with the outer mitochondrial membrane. Together, these results suggest that Parkin may promote the degradation of substrates localized in mitochondria and involved in the late mitochondrial phase of ceramide-mediated cell death. Loss of this function may underlie the degeneration of nigral dopaminergic neurons in patients with Parkin mutations.
Hum Mol Genet 2003 Mar 01
PMID:Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. 1258 99

Parkinson's disease (PD) is a progressive neurodegenerative disease that is caused by a loss of neurons in the ventral midbrain. Parkinsonian patients often experience insomnia, parasomnias, and daytime somnolence. REM sleep behavior disorder (RBD) is characterized by vigorous movements during REM sleep, and may also be caused by neuronal degeneration in the central nervous system (CNS); however, the site of degeneration remains unclear. Both Parkinsonism and RBD become more prevalent with aging, with onset usually occurring in the sixties. Recent findings show that many individuals with RBD eventually develop Parkinsonism. Conversely, it is also true that certain patients diagnosed with Parkinsonism subsequently develop RBD. Postmortem examination reveals that Lewy bodies, Lewy neurites, and alpha-synuclein are found in brainstem nuclei in both Parkinsonism and RBD patients. In this article, we will discuss evidence that Parkinsonism and RBD are physiologically and anatomically linked, based on our animal experiments and other studies on human patients.
Mol Neurobiol 2003 Apr
PMID:Physiological and anatomical link between Parkinson-like disease and REM sleep behavior disorder. 1277 84

Parkinson's disease (PD) is a severe neurological disorder, characterized by the progressive degeneration of the dopaminergic nigrostriatal pathway and the presence of Lewy bodies (LBs). The discovery of genes responsible for familial forms of the disease has provided insights into its pathogenesis. Mutations in the parkin gene, which encodes an E3 ubiquitin-protein ligase involved in the ubiquitylation and proteasomal degradation of specific protein substrates, have been found in nearly 50% of patients with autosomal-recessive early-onset parkinsonism. The abnormal accumulation of substrates due to loss of Parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. Here, we demonstrate that Parkin interacts with, ubiquitylates and promotes the degradation of p38, a key structural component of the mammalian aminoacyl-tRNA synthetase complex. We found that the ubiquitylation of p38 is abrogated by truncated variants of Parkin lacking essential functional domains, but not by the pathogenic Lys161Asn point mutant. Expression of p38 in COS7 cells resulted in the formation of aggresome-like inclusions in which Parkin was systematically sequestered. In the human dopaminergic neuroblastoma-derived SH-SY5Y cell line, Parkin promoted the formation of ubiquitylated p38-positive inclusions. Moreover, the overexpression of p38 in SH-SY5Y cells caused significant cell death against which Parkin provided protection. Analysis of p38 expression in the human adult midbrain revealed strong immunoreactivity in normal dopaminergic neurons and the labeling of LBs in idiopathic PD. This suggests that p38 plays a role in the pathogenesis of PD, opening the way for a detailed examination of its potential non-canonical role in neurodegeneration.
Hum Mol Genet 2003 Jun 15
PMID:The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration. 1278 50

Among the phenotypes associated with Gaucher disease, the deficiency of glucocerebrosidase, are rare patients with early onset, treatment-refractory parkinsonism. Sequencing of glucocerebrosidase in 17 such patients revealed 12 different genotypes. Fourteen patients had the common "non-neuronopathic" N370S mutation, including five N370S homozygotes. While brain glucosylsphingosine levels were not elevated, Lewy bodies were seen in the four brains available for study. The shared clinical and neuropathologic findings in this subgroup suggest that the deficiency in glucocerebrosidase may contribute to a vulnerability to parkinsonism.
Mol Genet Metab 2003 Jun
PMID:Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? 1280 40


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