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)

The entorhinal territory consists of the entorhinal and transentorhinal regions spreading over the ambient gyrus and anterior portions of the parahippocampal gyrus. The transentorhinal region mediates between the adjoining temporal isocortex laterally and the entorhinal region medially. The entorhinal cortex consists of a molecular layer, followed by an external principal stratum, a cell-sparse lamina dissecans, an internal principal stratum and--within the underlying white matter--a profound cellular layer. The principal strata can each be divided into three layers Pre alpha, beta, gamma, and Pri alpha, beta, gamma. Data obtained from experimental investigations in monkeys reveal that the entorhinal territory serves as a relay station for information from both isocortical association areas and centers of the limbic system. After processing within the entorhinal cortex, this information is transferred to the hippocampal formation via the perforant path. Pathological changes within the entorhinal territory impair this continuous data transfer and contribute to a decline of cognitive functions. Entorhinal involvement associated with impaired cognitive functions is described in cases of Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, dementia with argyrophilic grains and Huntington's disease.
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PMID:The human entorhinal cortex: normal morphology and lamina-specific pathology in various diseases. 133 86

The basal ganglia and substantia nigra, taken from control human brain and from patients dying with a diagnosis of Parkinson's disease or Huntington's chorea, were analysed with histochemical and biochemical techniques. The pigmented neurons of the substantia nigra pars compacta possess tyrosine hydroxylase immunoreactivity and are disposed in three major layers, alpha, beta and gamma. This pattern became obscured in choreic brains by the severe shrinkage of the nigra, but total numbers of pigmented neurons were within the normal range. In contrast, pigmented neurons were lost from all layers of the substantia nigra in Parkinson's disease, although examination of cases with minimal cell loss suggested that an internal part of the lateral alpha sub-layer was most severely and consistently affected. A dopaminergic projection between this internal part of the alpha sub-layer and the putamen was suggested by the preferential loss of catecholamines from the putamen in Parkinson's disease. The distribution of the peptides, substance P, methionine-enkephalin and dynorphin 1-17 were mapped immunohistochemically within the substantia nigra. The different patterns of immunoreactive axons and terminals were found to be extensive, at least partially overlapping, and largely avoided the region of the pigmented perikarya of the alpha sub-layer and nucleus paranigralis. All peptides were depleted in choreic substantia nigra, reflecting the degeneration of the striatonigral pathway. However, concentrations of enkephalin-like immunoreactivity were increased within the interpeduncular nucleus. In Parkinson's disease there was a loss of enkephalin- and dynorphin-like immunoreactivity from the substantia nigra but a fall in substance P-like immunoreactivity was only detected by radioimmunoassay, not by immunocytochemistry. Peptide immunoreactivity was also reduced within choreic basal ganglia. However, no gross changes were found in peptide staining of the parkinsonian basal ganglia. In summary we have reported a number of changes in peptide-containing pathways in human degenerative disorders that may reflect the degeneration of neuronal pathways either as a primary event or secondary to initial lesion. We have also emphasized the sensitivity of the alpha sub-layer of nigral neurons to damage in Parkinson's disease. We suggest that the lower density of peptidergic fibres in the area of the perikarya may contribute to the susceptibility of these neurons to damage.
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PMID:Immunocytochemical studies on the basal ganglia and substantia nigra in Parkinson's disease and Huntington's chorea. 245 87

Mofegiline or MDL 72,974A ((E)-4-fluoro-beta-fluoromethylene benzene butanamine hydrochloride) is a selective enzyme-activated irreversible inhibitor of monoamine oxidase B, which is under development for use in the treatment of Parkinson's disease. Male beagle dogs were given single p.o. (20 mg/kg) and i.v. (5 mg/kg) doses of [14C]-Mofegiline. Total radioactivity excreted in urine and feces over 96 hr was, respectively, 75.5 +/- 3.8 and 6.3 +/- 3.4% of the dose after p.o. and 67.9 +/- 0.5 and 3.9 +/- 2.4% after i.v. administration. Unchanged drug in urine represented 3% of the dose after po and less than 1% after i.v. administration. Mofegiline was thus extensively metabolized in dogs, and urinary excretion was the major route of elimination of metabolites. HPLC, with on-line radioactivity detection, showed the presence of four major peaks (M1, M2, M3, and M4), representing respectively 50, 9, 5, and 0.5% of the administered dose excreted in 0-24 hr urine. TSP-LC-MS, FAB-MS, and NMR spectra of the purified metabolites were obtained. M1, the major metabolite in dogs, was shown to have undergone defluorination of the beta-fluoromethylene moiety, and one carbon addition. Its structure was confirmed to be a cyclic carbamate. M2 was a N-carbamoyl O-beta-D-glucuronide conjugate of parent drug. The formation of M1 and M2 is likely to involve initial reversible addition of CO2 to the primary amine function. M3 was a N-succinyl conjugate of the parent drug. M4 had also undergone defluorination to yield a urea adduct of an unsaturated alpha, beta aldehyde. Structures of M1 and M3 were further confirmed by comparing their MS and NMR spectra with those of authentic reference compounds. TSP-LC-MS ion chromatograms of human urine, obtained from two male volunteers after p.o. administration of 24 mg of drug, showed selected molecular ion peaks with the same retention time as the metabolites identified in dogs. In humans, these common metabolites represented a similar percentage of the administered dose to that in dogs. The present study demonstrates that NMR, TSP-LC-MS are complementary analytical techniques, which allow structural identification of unhydrolyzed drug conjugates. The formation of carbamates of amine-containing drugs may be more common than previously reported.
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PMID:Novel carbamate metabolites of mofegiline, a primary amine monoamine oxidase B inhibitor, in dogs and humans. 783 26

Alterations in protein kinase C (PKC) and myo-inositol 1,4,5-trisphosphate (IP3) receptors were studied in the autopsied human striata from 21 patients with Parkinson's disease (PD) (Yahr III, IV, and V), 8 patients with Huntington's disease (HD), and 23 age-matched and postmortem time-matched nonneurological controls. The concentrations of PKC and IP3 receptors were determined using [3H]4 beta-phorbol 12,13-dibutyrate (PDBu) and [3H]IP3 as respective ligands. Both the specific [3H]-PDBu and [3H]IP3 bindings were significantly reduced in the striata of Yahr V patients with dementia (PDD) and in that of HD patients, as compared to findings in the controls. These bindings were unchanged when all the PD patients without dementia, Yahr (III plus IV) patients, or Yahr V patients without dementia were compared with evidence from the controls. Immunoquantification of four PKC subspecies (alpha, beta I, beta II, and gamma) in the HD putamen revealed a selective reduction in the beta II-PKC immunoreactions. These results are supported by immunohistochemical findings in the rat brain that beta II-PKC is expressed in the striatal gabaergic efferent pathway, while the alpha-PKC is present in the nigrostriatal dopaminergic neurons. The neurochemical pathophysiology of PD differs between patients with and without dementia.
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PMID:Second messenger systems in brains of patients with Parkinson's or Huntington's disease. 809 76

The presynaptic protein alpha-synuclein has been implicated in both neuronal plasticity and neurodegenerative disease, but its normal function remains unclear. We described the induction of an amphipathic alpha-helix at the N terminus (exons 2-4) of alpha-synuclein upon exposure to phospholipid vesicles, and hypothesized that lipid-binding might serve as a functional switch by stabilizing alpha-synuclein in an active (alpha-helical) conformation. Others have shown that alpha and beta-synucleins inhibit phospholipase D (PLD), an enzyme involved in lipid-mediated signaling cascades and vesicle trafficking. Here, we report that all three naturally occurring synuclein isoforms (alpha, beta, and gamma-synuclein) are similarly effective inhibitors of PLD2 in vitro, as is the Parkinson's disease-associated mutant A30P. The PD-associated mutant A53T, however, is a more potent inhibitor of PLD2 than is wild-type alpha-synuclein. We analyze mutations of the alpha-synuclein protein to identify critical determinants of human PLD2 inhibition in vitro. Deletion of residues 56-102 (exon 4) decreases PLD2 inhibition significantly; this activity of exon 4 may require adoption of an alpha-helical conformation, as mutations that disrupt alpha-helicity also abrogate inhibition. Deletion of C-terminal residues 130-140 (exon 6) completely abolishes inhibitory activity. In addition, PLD2 inhibition is blocked by phosphorylation at serine 129 or at tyrosine residues 125 and 136, or by mutations that mimic phosphorylation at these sites. We conclude that PLD2 inhibition by alpha-synuclein is mediated by a lipid-stabilized alpha-helical structure in exon 4 and also by residues within exon 6, and that this inhibition can be modulated by phosphorylation of specific residues in exons 5 and 6.
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PMID:Structural determinants of PLD2 inhibition by alpha-synuclein. 1503 66

The synuclein family includes three isoforms, termed alpha, beta and gamma. alpha-Synuclein accumulates in various pathological lesions resulting from neurodegenerative disorders including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. However, neither beta- nor gamma-synuclein has been detected in Lewy bodies, and thus it is unclear whether these isoforms contribute to neurological pathology. In the present study, we used immunohistochemistry to demonstrate accelerated accumulation of beta- and gamma-synucleins in axonal spheroids in gracile axonal dystrophy (gad) mice, which do not express ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1). gamma-Synuclein immunoreactivity in the spheroids appeared in the gracile nucleus at 3 weeks of age and was maintained until 32 weeks. beta-Synuclein immunoreactivity appeared in spheroids around 12 weeks of age. In contrast, alpha-synuclein immunoreactivity was barely detectable in spheroids. Immunoreactivity for synaptophysin and ubiquitin were either faint or undetectable in spheroids. Given that UCH-L1 deficiency results in axonal degeneration and spheroid formation, our findings suggest that beta- and gamma-synuclein participate in the pathogenesis of axonal swelling in gad mice.
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PMID:Accumulation of beta- and gamma-synucleins in the ubiquitin carboxyl-terminal hydrolase L1-deficient gad mouse. 1530 32

alpha-Synuclein (alpha-syn) is a small protein of unknown function that is found aggregated in Lewy bodies, the histopathological hallmark of sporadic Parkinson disease and other synucleinopathies. Mutations in the alpha-syn gene and a triplication of its gene locus have been identified in early onset familial Parkinson disease. alpha-Syn turnover can be mediated by the proteasome pathway. A survey of published data may lead to the suggestion that overexpression of alpha-syn wild type, and/or their variants (A53T and A30P), may produce a decrease in proteasome activity and function, contributing to alpha-syn aggregation. To investigate the relationship between synuclein expression and proteasome function we have studied proteasome peptidase activities and proteasome subunit expression (alpha, beta-constitutive, and inducible) in mice either lacking alpha-syn (knock-out mice) or transgenic for human alpha-syn A30P (under control of PrP promoter, at a time when no clear gliosis can be observed). Similar studies are presented in PC12 cells overexpressing enhanced yellow fluorescent protein fusion constructs of human wild type, A30P, and A53T alpha-syn. In these cell lines we have also analyzed the assembly of 20 S proteasome complex and the degradation rate of a well known substrate of the proteasome pathway, Ikappabalpha. Overall the data obtained led us to the conclusion that alpha-synuclein expression levels by themselves have no significant effect on proteasome peptidase activity, subunit expression, and proteasome complex assembly and function. These results strengthen the suggestion that other mechanisms resulting in synuclein aggregation (not simply expression levels) may be the key to understand the possible effect of aggregated synuclein on proteasome function.
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PMID:alpha-Synuclein expression levels do not significantly affect proteasome function and expression in mice and stably transfected PC12 cell lines. 2712 95

The members of the casein kinase 1 (CK1) family are highly conserved and are expressed in many eukaryotes ranging from yeast to humans. Mammalian CK1 isoforms (alpha, beta, gamma, delta, epsilon) and their splice variants are involved in diverse cellular processes including membrane trafficking, circadian rhythm, cell cycle progression, chromosome segregation, apoptosis and cellular differentiation. Mutations and deregulation of CK1 expression and activity has been linked to various diseases including neurodegenerative disorders such as Alzheimer's and Parkinson's disease, sleeping disorders and proliferative diseases such as cancer. In this review, we summarize the functions of CK1 and outline the participation of CK1 in signal transduction pathways linked to cancer development.
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PMID:The role of the casein kinase 1 (CK1) family in different signaling pathways linked to cancer development. 1618 92

Extensive changes in resting-state oscillatory brain activity have recently been demonstrated using magnetoencephalography (MEG) in moderately advanced, non-demented Parkinson's disease patients relative to age-matched controls. The aim of the present study was to determine the onset and evolution of these changes over the disease course and their relationship with clinical parameters. In addition, we evaluated the effects of dopaminomimetics on resting-state oscillatory brain activity in levodopa-treated patients. MEG background oscillatory activity was studied in a group of 70 Parkinson's disease patients with varying disease duration and severity (including 18 de novo patients) as well as in 21 controls that were age-matched to the de novo patients. Whole head 151-channel MEG recordings were obtained in an eyes-closed resting-state condition. Levodopa-treated patients (N = 37) were examined both in a practically defined 'OFF' as well as in the 'ON' state. Relative spectral power was calculated for delta, theta, low alpha, high alpha, beta and gamma frequency bands and averaged for 10 cortical regions of interest (ROIs). Additionally, extensive clinical and neuropsychological testing was performed in all subjects. De novo Parkinson's disease patients showed widespread slowing of background MEG activity relative to controls. Changes included a widespread increase in theta and low alpha power, as well as a loss of beta power over all but the frontal ROIs and a loss of gamma power over all but the right occipital ROI. Neuropsychological assessment revealed abnormal perseveration in de novo patients, which was associated with increased low alpha power in centroparietal ROIs. In the whole group of Parkinson's disease patients, longer disease duration was associated with reduced low alpha power in the right temporal and right occipital ROI, but not with any other spectral power measure. No association was found between spectral power and disease stage, disease severity or dose of dopaminomimetics. In patients on levodopa therapy, a change from the 'OFF' to the 'ON' state was associated with decreases in right frontal theta, left occipital beta and left temporal gamma power and an increase in right parietal gamma power. Widespread slowing of oscillatory brain activity is a characteristic of non-demented Parkinson's disease patients from the earliest clinical stages onwards that is (largely) independent of disease duration, stage and severity and hardly influenced by dopaminomimetic treatment. Some early cognitive deficits in Parkinson's disease appear to be associated with increased low alpha power. We postulate a role for hypofunctional non-dopaminergic ascending neurotransmitter systems in spectral power changes in non-demented Parkinson's disease patients.
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PMID:Slowing of oscillatory brain activity is a stable characteristic of Parkinson's disease without dementia. 1741 33

Increasing evidence suggests that abnormal oscillatory activity in basal ganglia and cortex plays a pivotal role in the pathophysiology of Parkinson's disease. Recordings of local field potentials from subthalamic nucleus of patients undergoing deep brain stimulation have focused on oscillations occurring at frequencies below 100 Hz in the alpha, beta and gamma range and suggested that, in particular, an increase of beta band oscillations underlies slowing of movement in Parkinson's disease. Recent findings showing that the amplitude of high frequency oscillations (>200 Hz) couples with the phase of beta activity have raised the important question about the role of subthalamic high frequency oscillations in Parkinson's disease. To investigate functional characteristics and clinical relevance of high frequency oscillations, we recorded local field potentials from 18 subthalamic nuclei of 9 akinetic-rigid Parkinsonian patients with implanted deep brain stimulation electrodes and still externalised leads before and after intake of levodopa. We identified two distinct bands of high frequency oscillations, one centred around 250 Hz and another one around 350 Hz that show characteristic levodopa dependent amplitude and coupling behaviours. Administration of levodopa changed the power ratio between the two high frequency bands towards the component centred around 350 Hz in all 18 nuclei under study (p<10(-4)). Moreover, this power ratio correlated significantly with the Unified Parkinson's Disease Rating Scale hemibody akinesia/rigidity subscore (r=0.3618, p=0.015), but interestingly not with beta peak power (p=0.1) suggesting that levodopa induced changes in high frequency and beta oscillations are at least potentially independent of each other. Accordingly, a combined parameter composed of power ratio of high frequency oscillations and beta peak power significantly increased the correlation with the motor state (r=0.45, p=0.004). These results indicate that a shift from slower to faster frequencies of the spectrum greater than 200 Hz represents a prokinetic neurophysiological marker underlying levodopa induced motor improvement in Parkinson's disease.
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PMID:High frequency oscillations in the subthalamic nucleus: a neurophysiological marker of the motor state in Parkinson's disease. 2137 39


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