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)

Melanin, the pigment in hair, skin, eyes, and feathers, protects external tissue from damage by UV light. In contrast, neuromelanin (NM) is found in deep brain regions, specifically in loci that degenerate in Parkinson's disease. Although this distribution suggests a role for NM in Parkinson's disease neurodegeneration, the biosynthesis and function of NM have eluded characterization because of lack of an experimental system. We induced NM in rat substantia nigra and PC12 cell cultures by exposure to l-dihydroxyphenylalanine, which is rapidly converted to dopamine (DA) in the cytosol. This pigment was identical to human NM as assessed by paramagnetic resonance and was localized in double membrane autophagic vacuoles identical to NM granules of human substantia nigra. NM synthesis was abolished by adenoviral-mediated overexpression of the synaptic vesicle catecholamine transporter VMAT2, which decreases cytosolic DA by increasing vesicular accumulation of neurotransmitter. The NM is in a stable complex with ferric iron, and NM synthesis was inhibited by the iron chelator desferrioxamine, indicating that cytosolic DA and dihydroxyphenylalanine are oxidized by iron-mediated catalysis to membrane-impermeant quinones and semiquinones. NM synthesis thus results from excess cytosolic catecholamines not accumulated into synaptic vesicles. The permanent accumulation of excess catechols, quinones, and catechol adducts into a membrane-impermeant substance trapped in organelles may provide an antioxidant mechanism for catecholamine neurons. However, NM in organelles associated with secretory pathways may interfere with signaling, as it delays stimulated neurite outgrowth in PC12 cells.
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PMID:Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. 1105 Feb 21

Monoamine compartmentalization in monoaminergic neurons uses serial action of the plasma membrane and vesicular monoamine (VAMT2) transporters. We can now define the sequences of the genes encoding these transporters in mice and humans, examine influences of deletions of this gene and alteration in its expression levels in transgenic mice, and identify sequence polymorphisms in the human VMAT2 gene. Examination of VMAT2 variants can provide potential insights into roles for allelic variants at these loci in variant drug responses and in diseases linked to monoaminergic systems, including substance abuse and Parkinson's disease.
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PMID:The VMAT2 gene in mice and humans: amphetamine responses, locomotion, cardiac arrhythmias, aging, and vulnerability to dopaminergic toxins. 1109 63

Mutations in alpha-synuclein have been linked to rare, autosomal dominant forms of Parkinson's disease. Despite its ubiquitous expression, mutant alpha-synuclein primarily leads to the loss of dopamine-producing neurons in the substantia nigra. alpha-Synuclein is a presynaptic nerve terminal protein of unknown function, although several studies suggest it is important for synaptic plasticity and maintenance. The present study utilized a new human mesencephalic cell line, MESC2.10, to study the effect of A53T mutant alpha-synuclein on dopamine homeostasis. In addition to expressing markers of mature dopamine neurons, differentiated MESC2.10 cells are electrically active, produce dopamine, and express wild-type human alpha-synuclein. Lentivirus-induced overexpression of A53T mutant alpha-synuclein in differentiated MESC2.10 cells resulted in down-regulation of the vesicular dopamine transporter (VMAT2), decreased potassium-induced and increased amphetamine-induced dopamine release, enhanced cytoplasmic dopamine immunofluorescence, and increased intracellular levels of superoxide. These results suggest that mutant alpha-synuclein leads to an impairment in vesicular dopamine storage and consequent accumulation of dopamine in the cytosol, a pathogenic mechanism that underlies the toxicity of the psychostimulant amphetamine and the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium. Interestingly, cells expressing A53T mutant alpha-synuclein were resistant to amphetamine-induced toxicity. Because extravesicular, cytoplasmic dopamine can be easily oxidized into reactive oxygen species and other toxic metabolites, mutations in alpha-synuclein might lead to Parkinson's disease by triggering protracted, low grade dopamine toxicity resulting in terminal degeneration and ultimately cell death.
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PMID:Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line. 1214 95

When infused in rats, rotenone, a mitochondrial complex I inhibitor, induces alterations that resemble the histological changes of Parkinson's disease, particularly degeneration of the nigrostriatal dopaminergic system. However, the specificity of rotenone effects has been challenged recently. We have re-examined the alterations caused by rotenone in the substantia nigra and the striatum of rats after infusion of rotenone (2 mg/kg per day s.c.) for 21 days. Three patterns of striatal tyrosine-hydroxylase immunoreactivity (TH-IR) were observed: 46% of animals showed no reduction, and 46% of animals showed diffuse reduction in TH-IR, whereas one animal presented a focal loss of TH-IR in the striatum. Confocal microscopy analysis showed that the vesicular monoamine transporter (VMAT2) was decreased in parallel with TH-IR, strongly suggesting a loss of striatal DA nerve terminals in animals with diffuse or central TH-IR loss. However, no significant loss of TH-IR neurons was observed in the substantia nigra. Analysis of NeuN and DARPP-32 immunoreactivity, and Nissl staining, in the striatum showed no striatal neuronal loss in animals with either preserved TH-IR or diffuse TH-IR reduction. However, in the animal with focal TH-IR loss, severe neuronal loss was evident in the center and the periphery of the striatum, together with microglial activation detected by OX-6 and OX-42 staining. Thus, in most cases, chronic subcutaneous infusion of low doses of rotenone does not induce significant striatal neuronal loss, despite TH-IR and VMAT-IR reduction in a subset of animals, supporting the use of rotenone as a model of Parkinson's disease under carefully controlled experimental conditions.
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PMID:Variable effects of chronic subcutaneous administration of rotenone on striatal histology. 1538 65

Numerous studies suggest that the dopamine transporter (DAT), responsible for dopamine reuptake, may act as a vulnerability factor in the pathogenesis of Parkinson's disease (PD) and the vesicular monoamine transporter (VMAT2), responsible for its vesicular storage, as a neuroprotective factor. However, the relevance of each on the differential vulnerability of midbrain DA cells remains unknown. Here we studied the relationship between the expression pattern (mRNA and protein) of both transporters and the differential vulnerability of midbrain DA cells in a model of PD (intracerebroventricular injection of 6-OHDA in rats) and in monkey and human midbrain. Our results revealed that the expression patterns for VMAT2 mRNA and protein and DAT mRNA are similar, with the highest levels in the rostromedial region of substantia nigra (SNrm), followed by the caudoventral region of SN (SNcv), the ventral tegmental area and pigmented parabrabraquial nucleus (VTA/PBP), and finally the linear and interfascicular nuclei (Li/IF). In contrast, the expression of DAT protein in rats, monkeys, and humans followed a caudoventrolateral-to-rostrodorsomedial decreasing gradient (SNcv > SNrm > VTA/PBP > Li/IF), matching the degeneration profile observed after intracerebroventricular injection of 6-OHDA and in PD. In addition, DAT blockade made all midbrain DA cells equally resistant to 6-OHDA. These data indicate that DAT protein levels, but not DAT mRNA levels, are closely related to the differential vulnerability of midbrain DA cells and that this relationship is unaffected by the relative levels of VMAT2. Furthermore, the difference between DAT mRNA and protein profiles suggests internuclear differences in its posttransductional regulation.
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PMID:Expression of dopamine and vesicular monoamine transporters and differential vulnerability of mesostriatal dopaminergic neurons. 1545 55

The extent to which genetic variation in a population contributes to phenotypic variation depends on the frequency of sequence polymorphisms and the effect of these polymorphisms on function. The frequency of polymorphisms might also reflect the severity of their effects on function. We therefore examined the effect of very rare single nucleotide polymorphisms (SNPs) on the activity of the vesicular monoamine transporter 2 (VMAT2, SLC18A2), a gene implicated in neuropsychiatric disease. Of the two rare SNPs identified in an ethnically diverse population, neither eliminates transport, but one that involves replacement of a highly conserved residue with a very similar amino acid impairs substrate recognition. This variant, and another affecting an unconserved residue, also affect inhibition by the clinically used drug reserpine. Because VMAT2 influences a form of toxicity similar to Parkinson's disease, we extended the analysis to two SNPs identified in a population with Parkinson's disease. These two SNPs have no detectable effect on most aspects of VMAT2 function, but one that affects a highly conserved residue may increase sensitivity to the inhibitor tetrabenazine. The results illustrate the relationship between conservation of the affected residue, the nature of the substitution and effects on substrate versus inhibitor interaction.
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PMID:The effect of rare human sequence variants on the function of vesicular monoamine transporter 2. 1547 32

Pramipexole (PRX) is a non-ergot dopamine (DA) D2/D3 receptor agonist. Experimental studies have provided evidence that PRX may exert neuroprotective effects on the nigro-striatal system. Recent studies have demonstrated a slower decline of DAT density in Parkinson's disease patients treated with PRX as measured by SPECT. The aim of this study is to determine whether PRX has direct biological effects on DAergic neuron-associated genes expression, including DAT, VMAT2, and Nurr1. The human neuroblastoma SH-SY5Y cells were treated with PRX for various time periods and harvested to measure the mRNA and protein products of these genes. Treatment with PRX at 10 microM significantly increased DAT mRNA levels by 54-130% in 4-8 h, VMAT2 mRNA levels by 34% in 4 h, and Nurr1 mRNA levels by 31-39% in 2-4 h, which was the earliest induction among these three genes. The protein levels of DAT, VMAT2, and Nurr1 were markedly increased after PRX treatment, among which the increase of Nurr1 protein level was the highest at first 2 h treatment of PRX. Nafadotride, a D3 DA receptor antagonist, blocked the increase of Nurr1 gene expression induced by PRX, while eticlopride, a D2 DA receptor antagonist, didn't show this effect. Our findings that PRX has biological regulatory effects on DAergic neuron-associated genes may explain both the slower decline of imaged DAT and the neuroprotective effect of PRX. Furthermore, our results suggest that the induction of Nurr1 gene expression by PRX may be mediated by D3 DA receptor.
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PMID:Biological effects of pramipexole on dopaminergic neuron-associated genes: relevance to neuroprotection. 1574 Aug 46

Idiopathic Parkinson's disease (PD) affects 2% of adults over 50 years of age. PD patients demonstrate a progressive loss of dopamine neurons in the substantia nigra pars compacta (SNpc). One model that recapitulates the pathology of PD is the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Here we show that exposure to an enriched environment (EE) (a combination of exercise, social interactions and learning) or exercise alone during adulthood, totally protects against MPTP-induced Parkinsonism. Furthermore, changes in mRNA expression would suggest that increases in glia-derived neurotrophic factors, coupled with a decrease of dopamine-related transporters (e.g. dopamine transporter, DAT; vesicular monoamine transporter, VMAT2), contribute to the observed neuroprotection of dopamine neurons in the nigrostriatal system following MPTP exposure. This non-pharmacological approach presents significant implications for the prevention and/or treatment of PD.
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PMID:Environmental enrichment in adulthood eliminates neuronal death in experimental Parkinsonism. 1579 May 41

The use of the potent neurotoxin MPTP in producing a model for Parkinson's disease (PD) has allowed us to dissect the cellular processes responsible for both selective neuronal vulnerability and neuroprotection in idiopathic PD. It has been suggested that vesicular monoamine transporters (VMATs) play a critical neuroprotective role in MPP+ toxicity. However, little is known about how this detoxificative sequestration in dopaminergic (DAergic) neurons is regulated at the molecular and cellular levels. Using the DAergic cell line MN9D as an in vitro model, we found that overexpression of VMAT2 (a neuronal isoform of VMATs) protects the transformants from MPP+-induced toxicity, consistent with the previous work on fibroblastic CHO cells. We further found that the MN9D cells displayed lower expression levels of secretory vesicle proteins such as synaptophysin. Overexpression of synaptophysin in MN9D cells can significantly increase the resistance of the transformants to MPP+ toxicity. The co-expression of VMAT2 and synaptophysin has shown synergistic protection for the transformants, suggesting a role of synaptophysin in the biogenesis of secretory vesicles and in influencing the targeting of VMAT2 to these vesicles. Our work indicates that both the expression level of VMAT2 and capacity of vesicular packaging of DA are important in protecting DAergic cells from MPP+ toxicity.
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PMID:Synaptophysin enhances the neuroprotection of VMAT2 in MPP+-induced toxicity in MN9D cells. 1602 84

Abnormal iron accumulations are frequently observed in the brains of patients with Parkinson's disease and in normal aging. Iron metabolism is regulated in the CNS by iron regulatory proteins (IRP-1 and IRP-2). Mice engineered to lack IRP-2 develop abnormal motoric behaviors including tremors at rest, abnormal gait, and bradykinesia at middle to late age (18 to 24 months). To further characterize the dopamine (DA) systems of IRP-2 -/- mice, we harvested CNS tissue from age-matched wild type and IRP-2 -/- (16-19 months) and analyzed the protein levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter (VMAT2), and DA levels in dorsal striatum, ventral striatum (including the core and shell of nucleus accumbens), and midbrain. We further analyzed the phosphorylation of TH in striatum at serine 40, serine 31, and serine 19. In both dorsal and ventral striatum of IRP-2 knockout mice, there was a 20-25% loss of TH protein and accompanied by a approximately 50% increase in serine 40 phosphorylation above wild-type levels. No change in serine 31 phosphorylation was observed. In the ventral striatum, there was also a significant loss (approximately 40%) of DAT and VMAT2. Levels of DA were decreased (approximately 20%) in dorsal striatum, but turnover of DA was also elevated ( approximately 30%) in dorsal striatum of IRP-2 -/- mice. We conclude that iron misregulation associated with the loss of IRP-2 protein affects DA regulation in the striatum. However, the modest loss of DA and DA-regulating proteins does not reflect the pathology of PD or animal models of PD. Instead, these observations support that the IRP-2 -/- genotype may enable neurobiological events associated with aging.
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PMID:Neurochemical investigations of dopamine neuronal systems in iron-regulatory protein 2 (IRP-2) knockout mice. 1605 92


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