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)

Endogenous isoquinoline (IQ) derivatives structurally related to the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridine (MPP(+)) may contribute to dopaminergic neurodegeneration in Parkinson's disease. We addressed the importance of the DAT molecule for selective dopaminergic toxicity by testing the differential cytotoxicity of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (3, IQs; 4,3,4-dihydroisoquinolines and 15, 1,2,3,4-tetrahydroisoquinolines) as well as MPP(+) in non-neuronal and neuronal heterologous expression systems of the DAT gene (human embryonic kidney HEK-293 and mouse neuroblastoma Neuro-2A cells, respectively). Cell death was estimated using the MTT assay and the Trypan blue exclusion method. Nine isoquinolines and MPP(+) showed general cytotoxicity in both parental cell lines after 72hr with half-maximal toxic concentrations (TC(50) values) in the micromolar range. The rank order of toxic potency was: papaverine>salsolinol=tetrahydropapaveroline=1-benzyl-TIQ=norsalsolinol>tetrahydropapaverine>2[N]-methyl-salsolinol>2[N]-methyl-norsalsolinol>2[N]-Me-IQ(+)=MPP(+). Besides MPP(+), only the 2[N]-methylated compounds 2[N]-methyl-IQ(+), 2[N]-methyl-norsalsolinol and 2[N]-methyl-salsolinol showed enhanced cytotoxicity in both DAT expressing cell lines with 2- to 14-fold reduction of TC(50) values compared to parental cell lines. The rank order of selectivity in both cell systems was: MPP(+)>>2[N]-Me-IQ(+)>2[N]-methyl-norsalsolinol=2[N]-methyl-salsolinol. Our results suggest that 2[N]-methylated isoquinoline derivatives structurally related to MPTP/MPP(+) are selectively toxic to dopaminergic cells via uptake by the DAT, and therefore may play a role in the pathogenesis of Parkinson's disease.
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PMID:Selective dopaminergic neurotoxicity of isoquinoline derivatives related to Parkinson's disease: studies using heterologous expression systems of the dopamine transporter. 1191 43

Peroxynitrite (ONOO(-)) has been implicated as a causative factor in dopamine neuronal damage resulting from exposure to methamphetamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and it may be involved in the etiology of Parkinson's Disease. ONOO(-) causes a concentration-dependent and irreversible reduction in dopamine uptake by EM4 cells stably expressing the human dopamine transporter (hDAT). The effect of ONOO(-) is manifested as a reduction in V(max). Cysteine, dithiothreitol, glutathione, and N-acetyl-cysteine, reagents that interact directly with ONOO(-), prevent this inhibition, whereas a scavenger of hydroxyl radical (dimethylsulfoxide), hydrogen peroxide (catalase), and superoxide (superoxide dismutase) did not. Dopamine in the extracellular medium protects the hDAT from ONOO(-), whereas intracellular dopamine does not. Parachloromercuribenzoic acid and 2-aminoethyl methanethiosulfonate (MTSEA), which share with ONOO(-) the ability to modify cysteine sulfhydryls, also inhibit hDAT function. ONOO(-) treatment lowers cysteine-specific labeling of the hDAT by MTSEA-biotin, suggesting that ONOO(-) reacts with one or more cysteines in hDAT. A mutant of hDAT (X7C) in which all intracellular and extracellular loop cysteines were mutated was resistant to inhibition by ONOO(-). Sensitivity to ONOO(-) was restored in mutants of hDAT in which reduced cysteines were present only in the first (C135) and third (C342) intracellular loops (CD-DAT), or in which C342 alone had been reintroduced into X7C (X7C-M342C). These results indicate that the hDAT is inhibited by ONOO(-) through oxidation of cysteine 342. Our studies also substantiate the possibility that drugs known to decrease DAT function in vivo (e.g., methamphetamine and MPTP) may exert their effects through ONOO(-)-mediated oxidative stress.
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PMID:Peroxynitrite inactivates the human dopamine transporter by modification of cysteine 342: potential mechanism of neurotoxicity in dopamine neurons. 1204 46

One of the most useful treatments of Parkinson's disease (PD) is dihydroxyphenylalanine (L-DOPA) administration. However, L-DOPA has been suggested to be toxic to dopamine (DA) neurons and perhaps contribute to the progression of the disease. Sequestration of DA and dopaminergic neurotoxins into vesicles by the vesicular monoamine transporter 2 (VMAT2) is a key factor in preventing cellular damage. Mice with reduced expression of VMAT2 (VMAT2 heterozygote knockout mice; VMAT2 (+/-)) are more sensitive to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine. In this study, we subjected VMAT2 (+/-) mice to subchronic administration of L-DOPA to determine if it was toxic in this model. VMAT2 wild-type (VMAT2 (+/+)) and VMAT2 (+/-) mice were given i.p. injections of L-DOPA:carbidopa (50:5 mg/kg) three times a day for 28 days. Biochemical analysis revealed a significant increase in striatal DA levels in both groups of mice treated with L-DOPA. L-DOPA treatment significantly decreased DAT levels in VMAT2 (+/+) mice, but not in VMAT2 (+/-) mice. VMAT2 protein levels, an index of terminal integrity and the number of tyrosine hydroxylase (TH)-positive nigral cells remained unchanged after L-DOPA treatment. These data indicate that in an animal model that displays increased susceptibility to dopaminergic injury, a subchronic administration of L-DOPA does not induce toxicity.
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PMID:L-DOPA does not cause neurotoxicity in VMAT2 heterozygote knockout mice. 1242 33

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.
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PMID:Clinical impact of diagnostic SPET investigations with a dopamine re-uptake ligand. 1245 97

Alpha-synuclein accumulates in Lewy bodies in idiopathic Parkinson's disease. Neither the normal function nor contribution of alpha-synuclein to the pathophysiology of neurodegeneration is known. Here we show that a normal function of alpha-synuclein is the negative modulation of human dopamine transporter (hDAT) activity. In cotransfected Ltk(-) cells, alpha-synuclein attenuated the reuptake of dopamine by hDAT, in a manner dependent on expression levels of alpha-synuclein. Alpha-synuclein-mediated inhibition of hDAT activity was independent of expression vectors, cell types and methods of transfection. The alpha-synuclein-mediated decrease in DAT activity occurred through diminished uptake velocity of dopamine, without changes in the affinity of hDAT for dopamine. Co-immunoprecipitation studies confirmed the formation of a stable complex between alpha-synuclein and DAT, through direct protein:protein interactions. Thus, under normal (non-toxic) expression conditions, alpha-synuclein negatively modulates dopamine uptake by DAT.
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PMID:Attenuation of dopamine transporter activity by alpha-synuclein. 1267 38

1. The ability to target specific neurons can be used to produce selective neural lesions and potentially to deliver therapeutically useful moieties for treatment of disease. In the present study, we sought to determine if a monoclonal antibody to the dopamine transporter (anti-DAT) could be used to target midbrain dopaminergic neurons. 2. The monoclonal antibody recognizes the second, large extracellular loop of DAT. The antibody was conjugated to the "ribosome-inactivating protein"; saporin, and stereotactically pressure microinjected into either the center of the striatum or the left lateral ventricle of adult, male Sprague-Dawley rats. 3. Local intrastriatal injections produced destruction of dopaminergic neurons in the ipsilateral substantia nigra consistent with suicide transport of the immunotoxin. Intraventricular injections (i.c.v.) produced significant loss of dopaminergic neurons in the substantia nigra and ventral tegmental area bilaterally without evident damage to any other aminergic structures such as the locus coeruleus and raphe nuclei. To confirm the anatomic findings, binding of [3-H]mazindol to DAT in the striatum and midbrain was assessed using densitometric analysis of autoradiograms. Anti-DAT-saporin injected i.c.v. at a dose of 21 microg, but not 8 microg, produced highly significant decreases in mazindol binding consistent with loss of the dopaminergic neurons. 4. These results show that anti-DAT can be used to target midbrain dopaminergic neurons and that anti-DAT-saporin may be useful for producing a lesion very similar to the naturally occurring neural degeneration seen in Parkinson's disease. Anti-DAT-saporin joins the growing list of neural lesioning agents based on targeted cytotoxins.
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PMID:Destruction of midbrain dopaminergic neurons by using immunotoxin to dopamine transporter. 1451 35

Parkinson's syndrome (PS) is frequently encountered in disorders associated with prominent degeneration of the nigrostriatal pathway as in Parkinson's disease, multisystem atrophy, and progressive supranuclear palsy (presynaptic PS). Drug-induced parkinsonism, a common, underdiagnosed health problem and psychogenic parkinsonism are causes of Parkinson's syndrome which, evidence suggests, occurs without degeneration of nigrostriatal structures. We review clinical features and results of DAT imaging in drug-induced parkinsonism and psychogenic parkinsonism. These two conditions normally give normal striatal DAT imaging results; an abnormal result in either case could exclude both conditions, corroborating a diagnosis of organic parkinsonism in uncertain cases.
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PMID:DAT imaging in drug-induced and psychogenic parkinsonism. 1453 Oct 43

Alpha-synuclein modulates dopamine homeostasis in dopamine-producing neurons of substantia nigra, partly through regulation of human dopamine transporter (hDAT) activity. To identify the underlying mechanisms, we disrupted the modulation of hDAT activity by wild-type (wt) alpha-synuclein, and its familial Parkinson's disease linked mutants A30P and A53T, by mild trypsinization (0.1%, 30 s) of Ltk(-) cotransfected cells. Trypsin completely reversed the attenuation of hDAT function mediated by wt and the A30P mutant. In A53T coexpressing cells, where DAT activity is not downregulated, trypsinization did not induce any changes. These effects of trypsin were mimicked by collagenase I and Dispase (0.1%, 1 min each) but not by chymotrypsin, Pronase, or papain (0.1%, up to 2 min each). Trypsin increased dopamine uptake in rat primary mesencephalic neurons, suggesting that DAT activity is also subjected to modulation by alpha-synuclein in these neurons that endogenously coexpress both proteins. In trypsinized cells, dopamine accelerated both production of reactive oxygen species and cell death in hDAT and wt or A30P, but not A53T, coexpressing cells, compared to nontrypsinized cells. Paradoxically, trypsin increased the protein-protein interactions between the synuclein variants and hDAT, without any noticeable proteolysis of these proteins. hDAT-alpha-synuclein protein-protein interactions occurred through residues 58-107 (NAC domain) of the alpha-synuclein variants and residues 598-620 of the carboxy-terminal tail of hDAT, in both trypsinized and nontrypsinized cells. Confocal microscopy and biotinylation studies show that, in cells expressing the wt or A30P variants, but not the A53T mutant, hDAT is sequestered away from the plasma membrane into the cytoplasm, an effect that is reversed by trypsin. These results show that alpha-synuclein modulates hDAT function through trafficking of the transporter in a process that can be disrupted by trypsin.
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PMID:Trypsin disrupts the trafficking of the human dopamine transporter by alpha-synuclein and its A30P mutant. 1475 60

For cell replacement therapy of neurodegenerative diseases such as Parkinson's disease (PD), methods for efficiently generating midbrain dopaminergic (DA) neurons from embryonic stem (ES) cells have been investigated. Two aspects of DA neuron generation are considered: genetic modification and manipulation of culture conditions. A transcription factor known as critical for development of DA neurons, Nurr1, was introduced into ES cells to see how they facilitate the generation of DA neurons from ES cells. Also, two culture procedures, the 5-stage method and stromal cell-derived inducing activity (SDIA) method, were used for ES cell differentiation. Using the 5-stage method, we and others previously demonstrated that Nurr1-overexpressing ES cells, under treatment of signaling molecules such as SHH and FGF8 followed by treatment of ascorbic acid, can differentiate into DA neurons with a high efficiency (> 60% of TH+/Tuj1+ neurons). Furthermore, using the SDIA method with treatment of signaling molecules, we found that Nurr1-overexpressing ES cells can differentiate to DA neurons with the highest efficiency ever reported (approximately 90% of TH+/Tuj1+ neurons). Importantly, our semi-quantitative and real-time PCR analyses demonstrate that all known DA marker genes (e.g., TH, AADC and DAT) were up-regulated in Nurr1- overexpressing ES cells when compared to the na ve ES cells. These cells produced increased dopamine compared to na ve D3 cells after differentiation. In the in vivo context after transplantation, the genetically modified ES cells also showed the highly increased dopaminergic neuronal phenotypes. Thus, the combination of genetic engineering and appropriate culture conditions provides a useful tool to generate a good cell source from ES cells for cell replacement therapy of degenerative diseases such as PD.
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PMID:Efficient induction of dopaminergic neurons from embryonic stem cells for application to Parkinson's disease. 1562 19

Parkinson's disease (PD) is, to a large extent, specific to the human species. Most symptoms are the consequence of the preferential degeneration of the dopamine-synthesizing cells of the mesostriatal-mesocortical neuronal pathway. Reasons for that can be traced back to the evolutionary mechanisms that shaped the dopamine neurons in humans. In vertebrates, dopamine-containing neurons and nuclei do not exhibit homogenous phenotypes. In this respect, mesencephalic dopamine neurons of the substantia nigra and ventral tegmental area are characterized by a molecular combination (tyrosine hydroxylase, aromatic amino acid decarboxylase, monoamine oxidase, vesicular monoamine transporter, dopamine transporter--to name a few), which is not found in other dopamine-containing neurons of the vertebrate brain. In addition, the size of these mesencephalic DA nuclei is tremendously expanded in humans as compared to other vertebrates. Differentiation of the mesencephalic neurons during development depends on genetic mechanisms, which also differ from those of other dopamine nuclei. In contrast, pathophysiological approaches to PD have highlighted the role of ubiquitously expressed molecules such as a-synuclein, parkin, and microtubule-associated proteins. We propose that the peculiar phenotype of the dopamine mesencephalic neurons, which has been selected during vertebrate evolution and reshaped in the human lineage, has also rendered these neurons particularly prone to oxidative stress, and thus, to the fairly specific neurodegeneration of PD. Numerous evidence has been accumulated to demonstrate that perturbed regulation of DAT-dependent dopamine uptake, DAT-dependent accumulation of toxins, dysregulation of TH activity as well as high sensitivity of DA mesencephalic neurons to oxidants are key components of the neurodegeneration process of PD. This view points to the contribution of nonspecific mechanisms (alpha-synuclein aggregation) in a highly specific cellular environment (the dopamine mesencephalic neurons) and provides a robust framework to develop novel and rational therapeutic schemes in PD.
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PMID:The degeneration of dopamine neurons in Parkinson's disease: insights from embryology and evolution of the mesostriatocortical system. 1568 11


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