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)

Twelve patients with long-standing Parkinson's disease, treated successfully with a combination of l-dopa and an inhibitor of aromatic l-amino acid decarboxylase (Ro 4-4602), in the ratio 4:1, were screened for damage to various organ systems, in particular liver and skeleton. Among other tests, liver biopsies were obtained before and after 6 months of treatment. One patient discontinued therapy becuase of an accentuation of pre-existent liver damage, another because of psychomental manifestations. The remaining ten patients were followed for 8-15 months and longer. The liver biopsies remained practically unaltered. Elevation of alkaline phosphatase was found in 10 out of 12 subjects. In five patients this rise fluctuated around the upper limit of normal. In two patients, who discontinued the treatment, the raised alkaline phosphatase values soon returned to normal. Analysis of isozymes proved this phosphatase to be of liver origin. All other liver function tests remained unchanged, except for an increased retention of bromsulphalein in two patients. In the one patient with the initially damaged liver, all tests became normal soon after discontinuation of therapy. No changes could be found in gastric acid secretion. All other parameters studied remained within normal limits, including urinary excretion of calcium and phosphate.
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PMID:Liver function and gastric acid secretion in parkinsonian patients under prolonged treatment with L-dopa and a peripheral decarboxylase inhibitor. 125 4

The major neuropathology of Parkinson's disease (PD) is the degeneration of nigrostriatal dopamine (DA), resulting in a deficiency of DA, and of the enzyme tyrosine hydroxylase (TH), which catalyzes the synthesis of L-dopa. The symptomatic treatment of PD consists of replenishing DA by administering L-dopa, which is enzymatically converted to DA in the striatum. The increase of TH activity by modification of the enzyme leads to an increased synthesis of striatal L-dopa, and thereby replenishes the missing DA more efficiently. The activity of TH is increased by protein kinase-dependent phosphorylation of the enzyme or by inhibition of dephosphorylation with specific phosphatase inhibitors. Thus, modification of TH results in an activated form of the enzyme, which might provide a basis for developing new strategies in the treatment of PD. The extraneuronal enzyme, catechol-O-methyl transferase (COMT), inactivates catecholamines by O-methylation, and its inhibition leads to increased levels of striatal DA. The availability of selective and nontoxic COMT inhibitors makes it possible to assess their therapeutic role in treatment of PD. The intraneuronal enzymes, monoamine oxidase (MAO)-A and MAO-B, inactivate catecholamines and other biogenic amines, such as serotonin, by deamination. Inhibition of these enzyme activities leads to increased levels of striatal DA. The irreversible MAO-B inhibitor selegiline was shown to exert antiparkinsonian activity, especially in the early stages of parkinsonism. Selegiline also prevents the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in MPTP-treated mice and monkeys. Its role in the prevention of the disease is under investigation in several clinical centers.
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PMID:The role of the regulatory enzymes of catecholamine synthesis in Parkinson's disease. 834 92

A monoclonal antibody, termed NFT200, was raised after in vitro immunization with sonicated neurofibrillary tangle (NFT)-enriched fractions prepared from Alzheimer brain. The antigen to which NFT200 is directed was expressed in the paired helical filaments of NFT in sporadic and familial Alzheimer disease (AD), in the straight filaments of NFT in AD, progressive supranuclear palsy and of Pick bodies, and the NFT in several other conditions such as Parkinson-dementia complex of Guam and subacute sclerosing panencephalitis. Granulovacuolar degeneration of AD was also labeled with NFT200. Hirano bodies and amyloid deposits in AD, as well as Lewy bodies of idiopathic Parkinson disease lacked in the antigen. The NFT200-antigen was also expressed as a phosphatase-insensitive antigen in normal neurofilaments found in spinal cord and peripheral nerve axons but was absent from the perikaryal accumulation of neurofilaments induced by aluminum intoxication. Nevertheless, immunoblot studies failed to detect the NFT200 in isolated preparations of the neurofilament proteins, MAP-2, tau, ubiquitin or A4-amyloid peptide. The results indicate that the NFT200 monoclonal antibody is directed against a phosphatase-insensitive epitope of an axonal protein associated with neurofilaments but is labile to isolation and expressed as a stable epitope of a 200 kDa component of NFT.
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PMID:Demonstration of a novel neurofilament associated antigen with the neurofibrillary pathology of Alzheimer and related diseases. 171 69

Using radioimmunoassay methods the authors assayed the concentration of biochemical neoplasm markers (BMN) in 106 patients with neurological diseases (M-56, F-50) in the serum, and in 20 cases in the cerebrospinal fluid. In certain cases these markers were present, and sometimes their concentration was raised: ferritin in multiple sclerosis from 200 to 1365 ng/ml, in ischaemic stroke up to 327.9 ng/ml, in Parkinson's disease up to 423 ng/ml in the serum. In some cases of other diseases the levels of carcinoembryonic antigen (CEA), acid prostatic phosphatase (PAP) and alpha-fetoprotein (AFP) were raised, similarly as that of human chorionic gonadotropin (HCG). Further studies are being conducted on BMN, including also other markers (CA 125, CA 199), with monoclonal antibodies, beta-endorphins and prostaglandins in neurological diseases, including multiple sclerosis. It is suggested (Nowak) that BMN may have an indirect role in the aetiology and pathogenesis of certain diseases of the nervous system and that they may have connections with prostaglandins.
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PMID:[Biochemical neoplasm markers in selected neurological diseases]. 243 40

This study was undertaken to evaluate the levels of cAMP-regulated phosphoproteins in the striatum of patients with neurodegenerative diseases of the dopaminergic system. Postmortem samples of caudate nucleus and putamen from 24 control subjects, 23 patients with Parkinson disease, and 13 patients with progressive supranuclear palsy were studied with immunoblotting techniques. The levels of tyrosine hydroxylase were reduced in patients with Parkinson disease (levels were 24% and 10% of controls in caudate nucleus and putamen, respectively) and with progressive supranuclear palsy (levels were 11% and 6% of controls in caudate nucleus and putamen, respectively). Five phosphoproteins, which are present in striatal neurons and are likely to play a role in the postsynaptic actions of dopamine, were measured. These included ARPP-16, ARPP-19, ARPP-21 (cAMP-regulated phosphoproteins of Mr 16,000, 19,000, and 21,000, respectively), DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32,000), and phosphatase inhibitor I. The levels of these phosphoproteins were inversely correlated with postmortem delay. In brains of patients with Parkinson disease or progressive supranuclear palsy with postmortem delays comparable to those of controls, the levels of these proteins as well as those of synaptic (synapsin I and synaptophysin) and glial (glial fibrillary acidic protein and myelin basic protein) markers were not significantly modified. We conclude that the levels of several phosphoproteins involved in signal transduction in striatal neurons are not altered in Parkinson disease and progressive supranuclear palsy. This observation supports the view that the striatal output neurons are intact in both diseases.
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PMID:Striatal phosphoproteins in Parkinson disease and progressive supranuclear palsy. 292 45

Dopamine acting in the striatum is necessary for normal movement and motivation. Drugs that change striatal dopamine neurotransmission can have long-term effects on striatal physiology and behavior; these effects are thought to involve alterations in gene expression. Using the 6-hydroxydopamine lesion model of Parkinson's disease and differential display PCR, we have identified a set of more than 30 genes whose expression rapidly increases in response to stimulation of striatal dopamine D1 receptors. The induced mRNAs include both novel and previously described genes, with diverse time courses of expression. Some genes are expressed at near-maximal levels within 30 min, whereas others show no substantial induction until 2 hr or more after stimulation. Some of the induced genes, such as CREM, CHOP, and MAP kinase phosphatase-1, may be components of a homeostatic response to excessive stimulation. Others may be part of a genetic program involved in cellular and synaptic plasticity. A very similar set of genes is induced in unlesioned animals by administration of the psychostimulant cocaine or the antipsychotic eticlopride, although in distinct striatal cell populations. In contrast to some previously described early genes, most of the novel genes are not induced in cortex by apomorphine, indicating specificity of induction. Thus we have identified novel components of a complex, coordinated genetic program that is induced in striatal cells in response to various dopaminergic manipulations.
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PMID:A complex program of striatal gene expression induced by dopaminergic stimulation. 965 Dec 13

Characteristic changes involving interactions between dopamine and glutamate in striatal medium spiny neurons now appear to contribute to symptom production in Parkinson's disease (PD). The balance between kinase and phosphatase signaling modifies the phosphorylation state of glutamate receptors and thus their synaptic strength. Sensitization of spiny-neuron NMDA and AMPA receptors alters cortical glutamatergic input to the striatum and modifies striatal GABAergic output, and thus motor function. Conceivably, the pharmacological targeting of spiny-neuron mechanisms modified in PD will provide a safer and more effective therapy.
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PMID:Striatal dopamine- and glutamate-mediated dysregulation in experimental parkinsonism. 1105 25

Disturbance in phosphorylation/dephosphorylation can trigger apoptosis. Little is known as to its effects on mesencephalic dopamine neurons, the major neurons lost in Parkinson's disease. In this study, okadaic acid (OKA), a phosphatase 1 and 2A inhibitor, with greater potency toward 2A, was toxic to mesencephalic dopamine and gamma-aminobutyric acid (GABA) neurons, however, dopamine neurons were 4-fold more sensitive. The EC(50) for dopamine versus GABA toxicity was 1.5 versus 6.5 nM, respectively, and was consistent with an inhibition of phosphatase 2A. Dopamine neurons were also more sensitive to calyculin-A, a phosphatase inhibitor equipotent toward 1 and 2A. OKA-methyl-ester, which lacks phosphatase inhibitory activity, was without effect. DNA laddering typical of apoptosis was observed in cultures at a concentration that was specifically toxic to dopamine neurons (5 nM). In contrast to the sensitivity of mesencephalic neurons to phosphatase inhibition, inhibition of protein kinase activity with staurosporine or K252a showed little toxicity and protected neurons from OKA. Consistent with in vitro findings, infusion of 32 to 320 pmol of OKA into the left striatum of rats caused a dose-dependent loss of striatal dopamine without any loss of GABA 1 week following infusion. Acutely, OKA increased tyrosine hydroxylase activity, a phosphatase 2A substrate, and increased dopamine turnover. The above-mentioned findings demonstrate that dysregulation of phosphatase activity is detrimental to mesencephalic neurons, with dopamine neurons, in vitro and in vivo, being relatively more sensitive to phosphatase 2A inhibition. Disturbances in the phosphorylation control of proteins unique to dopamine neurons may contribute to their enhanced vulnerability to OKA exposure.
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PMID:Differential sensitivity of mesencephalic neurons to inhibition of phosphatase 2A. 1150 86

Chronically administered levodopa to Parkinson's disease (PD) patients ultimately produces alterations in motor response. Similarly, in 6-hydroxydopamine lesioned hemi-parkinsonian rats, chronic twice-daily administration of levodopa progressively shortens the duration of contralateral turning, an index of, the wearing-off fluctuations that occur in parkinsonian patients. The pathogenesis of these response alterations involves, in part, upregulation of corticostriatal glutamatergic synaptic transmission. Changes involving kinase and phosphatase signaling pathways within striatal dopaminoceptive medium-spiny neurons now appear to contribute to increased synaptic efficacy of glutamatergic receptors in these neurons. Glutamate-mediated striatal sensitization subsequently modifies basal ganglia output in ways that favor the appearance of parkinsonian motor complications. At the molecular level, transcriptional activation of striatal CREB and cdk5 may contribute to the persistent expression of these levodopa-induced response alterations. Conceivably, a safer and more effective therapy for PD can be provided by drugs that target signaling proteins within striatal spiny neurons or those that interact extracellularly with non-dopaminergic receptors such as AMPA and NMDA, adenosine, adrenergic, opioid, and serotonergic.
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PMID:Glutamate-mediated striatal dysregulation and the pathogenesis of motor response complications in Parkinson's disease. 1237 27

The causes of sporadic Parkinson's disease (PD) are poorly understood. 6-Hydroxydopamine (6-OHDA), a PD mimetic, is widely used to model this neurodegenerative disorder in vitro and in vivo; however, the underlying mechanisms remain incompletely elucidated. We demonstrate here that 6-OHDA evoked endoplasmic reticulum (ER) stress, which was characterized by an up-regulation in the expression of GRP78 and GADD153 (Chop), cleavage of procaspase-12, and phosphorylation of eukaryotic initiation factor-2 alpha in a human dopaminergic neuronal cell line (SH-SY5Y) and cultured rat cerebellar granule neurons (CGNs). Glycogen synthase kinase-3 beta (GSK3beta) responds to ER stress, and its activity is regulated by phosphorylation. 6-OHDA significantly inhibited phosphorylation of GSK3beta at Ser9, whereas it induced hyperphosphorylation of Tyr216 with little effect on GSK3beta expression in SH-SY5Y cells and PC12 cells (a rat dopamine cell line), as well as CGNs. Furthermore, 6-OHDA decreased the expression of cyclin D1, a substrate of GSK3beta, and dephosphorylated Akt, the upstream signaling component of GSK3beta. Protein phosphatase 2A (PP2A), an ER stress-responsive phosphatase, was involved in 6-OHDA-induced GSK3beta dephosphorylation (Ser9). Blocking GSK3beta activity by selective inhibitors (lithium, TDZD-8, and L803-mts) prevented 6-OHDA-induced cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), DNA fragmentations and cell death. With a tetracycline (Tet)-controlled TrkB inducible system, we demonstrated that activation of TrkB in SH-SY5Y cells alleviated 6-OHDA-induced GSK3beta dephosphorylation (Ser9) and ameliorated 6-OHDA neurotoxicity. TrkB activation also protected CGNs against 6-OHDA-induced damage. Although antioxidants also offered neuroprotection, they had little effect on 6-OHDA-induced GSK3beta activation. These results suggest that GSK3beta is a critical intermediate in pro-apoptotic signaling cascades that are associated with neurodegenerative diseases, thus providing a potential target site amenable to pharmacological intervention.
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PMID:Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death. 1513 87


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